JP2010509266A - Arylsulfonylpyrrolidines as 5-HT6 inhibitors - Google Patents

Abstract

The present invention relates to substituted pyrrolidine compounds of formula (I) wherein m, n, Ar, R ¹ and R ² are as defined in the specification. Methods of making the compounds and methods of using the compounds are disclosed.

Description

  The present invention relates to substituted pyrrolidine compounds, and related compositions, methods of use as therapeutic agents, and methods of making the same.

  The action of 5-hydroxytryptamine (5-HT) as the main regulatory neurotransmitter in the brain is 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5 -Mediated by several receptor families called HT7. Based on the high level of 5-HT6 receptor mRNA in the brain, it is said that 5-HT6 receptor may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT2 selective ligands and 5-HT6 selective ligands may be used in certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorder, mood disorder, Headache, Alzheimer's disease (enhanced cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic attacks, akathisia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD) Recognized as potentially useful in the treatment of withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and disorders related to spinal trauma and / or head trauma, such as hydrocephalus ing. Such compounds are also expected to be useful in the treatment of certain gastrointestinal (GI) disorders, such as bowel dysfunction. For example, BL Roth et al., J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, DR Sibley et al., Mol. Pharmacol., 1993, 43, 320-327, AJ Sleight et al. , Neurotransmission, 1995, 11, 1-5, and AJ Sleight et al., Serotonin ID Research Alert, 1997, 2 (3), 115-8.

  While several 5-HT6 and 5-HT2A modulators have been disclosed, there remains a need for compounds useful for modulating 5-HT6 receptor, 5-HT2A receptor, or both. Yes.

  The present invention provides compounds of formula I:

［式中、
ｍは、０〜４であり；
ｎは、０〜２であり；
Ａｒは、場合により置換されているアリール又は場合により置換されているヘテロアリールであり；
Ｒ^１は：
水素；
Ｃ_１−６−アルキル；
ヘテロ−Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｐ−Ｘ−（ＣＨ_２）_ｑ−Ｒ^ａであり；
ここで、
Ｘは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
ｐ及びｑは、それぞれ独立に０又は１であり；そして
Ｒ^ａは：
Ｃ_１−６アルキル；
Ｃ_１−６アルコキシ；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
ヒドロキシ；
アミノ；
Ｎ−Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
それぞれのＲ^２は、独立に：
ハロ；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６−アルキル；
シアノ；
ニトロ；
アミノ；
Ｎ−Ｃ_１−６アルキル−アミノ
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ；
ヒドロキシ−Ｃ_１−６アルコキシ；
−Ｏ−Ｃ（Ｏ）−ＣＨ（ＮＨ_２）Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｒ−Ｙ−（ＣＨ_２）_ｓ−Ｚ−（ＣＨ_２）_ｔ−Ｑ−（ＣＨ_２）_ｕ−Ｒ^ｂであり；
ここで、
ｒ、ｓ、ｔ及びｕは、それぞれ独立に０又は１であり；
Ｙ及びＱは、それぞれ独立に−Ｏ−、−ＮＲ^ｃ−又は結合であり；
Ｚは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
Ｒ^ｂは：
水素；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６アルキル；
シアノ；
アミノ；
Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
Ｒ^ｃは：
水素；又は
Ｃ_１−６アルキルである］で示される化合物又はその薬学的に許容しうる塩を提供する。

[Where:
m is 0-4;
n is 0-2;
Ar is optionally substituted aryl or optionally substituted heteroaryl;
R ¹ is:
hydrogen;
Ci- ₆ -alkyl;
Hetero-C _1-6 alkyl; or — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a ;
here,
X is —C (O) — or —SO ₂ —;
p and q are each independently 0 or 1; and R ^a is:
C _1-6 alkyl;
C _1-6 alkoxy;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
Hydroxy;
amino;
N—C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and each R ² is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero- _Ci-6 -alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 alkyl-amino N, N-di-C _1-6 alkylamino;
Hydroxy-C _1-6 alkoxy;
_{-O-C (O) -CH (} NH 2) C 1-6 alkyl; or _{- (CH 2) r -Y- (} CH 2) s -Z- (CH 2) t -Q- (CH 2) u It is a -R ^b;
here,
r, s, t and u are each independently 0 or 1;
Y and Q are each independently —O—, —NR ^c — or a bond;
Z is —C (O) — or —SO ₂ —;
R ^b is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ^c is:
It provides a compound or a pharmaceutically acceptable salt thereof represented by or a C _1-6 alkyl]; hydrogen.

  The present invention further provides compositions comprising the subject compounds, methods of making the subject compounds, and methods of using the subject compounds.

  The present invention provides substituted arylsulfonylpyrrolidine compounds, related compositions, methods of manufacture, and their use for the manufacture of a medicament for the prevention and treatment of central nervous system (CNS) diseases and gastrointestinal disorders. To do.

  All patents and publications mentioned in this disclosure are incorporated herein by reference in their entirety.

Definitions Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It should be noted.

  “Agonist” refers to a compound that enhances the activity of another compound or receptor site.

“Alkyl” means a monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having 1 to 12 carbon atoms. “Lower alkyl” refers to an alkyl group or moiety having 1 to 6 carbon atoms, ie, C ₁ -C ₆ alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like.

  “Alkylene” means a linear saturated divalent hydrocarbon group having 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, 2,2 -Means dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene and the like.

  “Alkenylene” is a linear unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as ethenylene (—CH═ CH-), 2,2-dimethylethenylene, propenylene, 2-methylpropenylene, butenylene, pentenylene and the like.

  “Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

  “Alkoxyalkyl” means a moiety of the formula —R′—R ″, where R ′ is alkylene and R ″ is alkoxy, as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2- Methoxyethyl) -3-methoxypropyl is included.

  “Alkylcarbonyl” means a moiety of the formula —C (O) —R ″, where R ″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R ″, where R ′ is —SO ₂ — and R ″ is alkyl, as defined herein. is there.

“Alkylsulfonylalkyl” means a moiety of the formula R ^a —SO ₂ —R ^b —, where R ^a is alkyl and R ^b is alkylene, as defined herein. It is. Exemplary alkylsulfonylalkyl groups include, by way of example, 3-methanesulfonylpropyl, 2-methanesulfonylethyl, 2-methanesulfonylpropyl, and the like.

  “Aminoalkyl” refers to the group —R—R ′, where R ′ is amino and R is alkylene, as defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted one or two times with alkyl, providing “alkylaminoalkyl” and “dialkylaminoalkyl” respectively. “Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl, and the like. “Dialkylaminoalkyl” includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

  “Amidinyl” has the formula:

で示される基を意味し、ここで、各Ｒは独立に、本明細書で定義したように、水素またはアルキルである。

In which each R is independently hydrogen or alkyl as defined herein.

  “Amidinylalkyl” refers to the group —R—R ′, where R ′ is amidinyl and R is alkylene, as defined herein.

  “Amido” refers to the group —C (O) —NRR ′, where R and R ′ are each independently hydrogen or alkyl.

  “Antagonist” refers to a compound that diminishes or prevents the action of another compound or receptor site.

  “Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentarenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylide. Nyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperazinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl , Ethylenedioxyphenyl, and the like, including but not limited to partially hydrogenated derivatives thereof. Preferred aryls are phenyl and naphthyl, more preferably phenyl, but each of them may be optionally substituted as defined herein.

  “Aryloxy” means a moiety of the formula —OR, wherein R is an aryl moiety as defined herein.

“Arylalkyl” and “aralkyl” can be used interchangeably and refer to the group —R ^a R ^b , where R ^a is an alkylene group, as defined herein, and R ^b Is an aryl group; for example, phenylalkyl such as benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl.

  “Aralkoxy” means a moiety of the formula —OR, wherein R is an aralkyl moiety as defined herein.

  “Carbamyl” has the formula:

で示される基を意味し、ここで、Ｒ^ｇ及びＲ^ｈは、それぞれ独立に水素又はアルキルである。

Wherein R ^g and R ^h are each independently hydrogen or alkyl.

  “Cyanoalkyl” means a moiety of the formula —R′—R ″, wherein R ′ is alkylene as defined herein, and R ″ is cyano or nitrile.

  “Cycloalkyl” means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Unless otherwise specified, cycloalkyl can be optionally substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, mono Alkylamino or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as partially unsaturated derivatives thereof.

  “Cycloalkylalkyl” means a moiety of the formula —R′—R ″, where R ′ is alkylene and R ″ is cycloalkyl, as defined herein.

  As used herein, “guanidinyl” has the formula:

［式中、Ｒ、Ｒ′、Ｒ″及びＲ'''は、それぞれ独立に水素又はアルキルである］で示される基を意味する。

[Wherein, R, R ′, R ″ and R ′ ″ each independently represents hydrogen or alkyl].

“Heteroalkyl” means an alkyl group as defined herein, wherein 1, 2 or 3 hydrogen atoms are —OR ⁱ , —NR ⁱⁱ R ⁱⁱⁱ , and —S (O) _z. It is replaced by a substituent independently selected from the group consisting of R ^iv (where n is an integer from 0 to 2), and the bonding position of the heteroalkyl group is understood to be via a carbon atom. Where R ⁱ is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R ⁱⁱ and R ⁱⁱⁱ are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl ; and when z is ^0, if ^{R iv} is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and z is 1 or ^{2, R iv} is Alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples are 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl. 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylamino Examples include, but are not limited to, sulfonylpropyl and the like. A preferred heteroalkyl is hydroxy-C _1-6 alkyl.

  “Heteroaryl” has at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, with the remaining ring atoms being C. It is understood that the monocyclic or bicyclic group having 5 to 12 ring atoms is present, and the bonding position of the heteroaryl group is on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, Quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, Quinolidinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acryl Cycloalkenyl include such, but also includes their partially hydrogenated derivatives, and the like. Preferred heteroaryl residues are indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl, or benzoimidazolyl, each optionally substituted as defined herein.

  “Heteroaryloxy” means a moiety of the formula —OR, wherein R is a heteroaryl moiety as defined herein.

“Heteroarylalkyl” and “heteroaralkyl” may be used interchangeably and refer to the group —R ^a R ^b , where R ^a is an alkylene group, as defined herein. And R ^b is a heteroaryl group.

  “Heteroaralkoxy” means a moiety of the formula —OR, wherein R is a heteroaralkyl moiety as defined herein.

  The terms “halo” and “halogen” may be used interchangeably and refer to the substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogen has been replaced by same or different halogen. Exemplary haloalkyl includes —CH ₂ Cl, —CH ₂ CF ₃ , —CH ₂ CCl ₃ , perfluoroalkyl (eg, —CF ₃ ), and the like.

  “Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

  “Hydroxyalkyl” refers to a subset of heteroalkyl, particularly alkyl moieties as defined herein, which are substituted by one or more, preferably 1, 2, or 3 hydroxy groups, provided that The same carbon atom shall not carry more than one hydroxy group. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy Butyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl. It is not limited to.

  “Heterocycloamino” means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

  “Heterocyclyl” means a monovalent saturated moiety consisting of 1 to 3 rings and incorporating 1, 2, or 3 or 4 heteroatoms (selected from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, azolidinyl, azolidinyl, azolidinyl, Lysinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolidinyl, benzothiazolidinyl, benzoazolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide , Thiamorpholinyl sulfone, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydro Sokinoriniru Although etc., not limited thereto.

  “Heterocyclylalkyl” refers to the group —R—R ′ where R ′ is heterocyclyl as defined herein and R is alkylene.

  As used herein, “imidazolinyl” has the formula:

［式中、Ｒ′は、水素又はアルキルである］で示される基を意味する。イミダゾリニル基は、場合により、本明細書で定義したように置換されていてもよい。

Wherein R ′ is hydrogen or alkyl. The imidazolinyl group may be optionally substituted as defined herein.

  “Imidazolinylalkyl” refers to the group —R—R ′, where R ′ is imidazolinyl as defined herein and R is alkylene.

  “Imidazolinylaminoalkyl” refers to the group —R—R′—R ″, where R ″ is imidazolinyl as defined herein, R ′ is amino, and R is Alkylene. The amino moiety of “imidazolinylaminoalkyl” may be optionally substituted by alkyl.

  “Pyrimidinylaminoalkyl” refers to the group —R—R′—R ″, where R ″ is pyrimidinyl (preferably pyrimidin-2-yl), R ′ is amino, and R is , Alkylene. The pyrimidinyl moiety of “pyrimidinylaminoalkyl” may be optionally substituted as defined herein, and the amino moiety of “pyrimidinylaminoalkyl” may be optionally substituted by alkyl. .

  “Tetrahydropyrimidinyl” means 1,4,5,6-tetrahydropyrimidinyl, preferably 1,4,5,6-tetrahydropyrimidin-2-yl, optionally as defined herein. May be substituted. “Tetrahydropyrimidinyl” includes 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl.

  “Tetrahydropyrimidinylaminoalkyl” refers to the group —R—R′—R ″, where R ″ is tetrahydropyrimidinyl, R ′ is amino, and R is alkylene. The amino moiety of “tetrahydropyrimidinylaminoalkyl” may be optionally substituted by alkyl.

  "Urea" has the formula:

［式中、Ｒ^ｇ、Ｒ^ｈ及びＲ^ｉは、それぞれ独立に水素又はアルキルである］で示される基を意味する。

[Wherein R ^g , R ^h and R ⁱ are each independently hydrogen or alkyl].

  “Urealkyl” refers to the group R—R ′, where R ′ is urea and R is alkylene.

“Optionally substituted” when used in connection with “aryl”, “phenyl”, “heteroaryl” or “heterocyclyl” means aryl, phenyl, heteroaryl or heterocyclyl; Is optionally alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, hetero Alkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), — (CR ^v R ^vi ) _y —COOR ^vii where y is an integer from 0 to 5; ^v and ^{R vi} are independently hydrogen or alkyl, ^{R v i} is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or ^- (with _{^{CR v R vi) y -CONR viii}} R ix ( where, y is an integer from 0 to 5 , R ^v and R ^vi are independently hydrogen or alkyl, and R ^viii and R ^ix are independently of each other hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Substituted by 1 to 4 substituents, preferably 1 or 2 substituents. A further optional substituent is — (CH ₂ ) _w —S (O) _x —R ^d , where w is 0 or 1, x is 0 to 2, and R ^d is Hydrogen, alkyl, haloalkyl, hydroxyl, heteroalkyl, amino, mono-alkylamino or di-alkylamino. Preferred optional substituents are halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro , Amino, N—C _1-6 alkyl-amino, N, N-di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x— R ^d , where w is 0 or 1, x is 0-2, R ^d is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, Hetero-C _1-6 alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino. Even more preferred optional substituents are halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl-amino, N , N-di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d , where w is 0 or a 1, x is 0 to 2, ^{R d} _{is, C 1-6} alkyl, halo _{-C 1-6} alkyl, _{amino, C 1-6} alkyl - amino, or N, N-di -C _1-6 alkylamino.

  “Leaving group” means a group having the meaning conventionally associated with it in synthetic organic chemistry, ie, an atom or group that can be replaced under substitution reaction conditions. Examples of leaving groups are halogen, alkane or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted Examples include, but are not limited to benzyloxy, isopropyloxy, acyloxy and the like.

  “Modulator” means a molecule that interacts with a target. As defined herein, interactions include, but are not limited to agonists, antagonists and the like.

  “Any” or “optional” means that the following described event or situation may occur, but does not have to occur, and the description does not occur with the case where the event or situation occurs Means including cases.

  “Disease” and “Disease state” means any disease, condition, symptom, disorder, or indication.

  “Inert organic solvent” or “inert solvent” means that the solvent is inert under the reaction conditions described therewith, for example benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, Including chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents.

  “Pharmaceutically acceptable” means veterinary medicine that is generally safe, non-toxic and useful in the preparation of pharmaceutical compositions that are not biologically or otherwise undesirable. As well as acceptable for pharmaceutical use in humans.

  "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid Citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , An acid addition salt formed with muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc .; For example, replaced by alkali metal ions, alkaline earth ions, or aluminum ions Are either salts formed when one of or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

  Preferred pharmaceutically acceptable salts are those formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.

  It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein for the same acid addition salt. is there.

  The terms “pro-drug” and “prodrug” may be used interchangeably and release the active parent drug of formula I in vivo when such prodrug is administered to a mammalian subject. Any of the compounds to be referred to. Prodrugs of compounds of formula I can be prepared by modifying one or more functional groups present in the compound of formula I to cleave in vivo to release the parent compound. A prodrug is a compound of formula I wherein the hydroxy, amino, or sulfhydryl group in the compound of formula I can be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Includes those optionally attached to a group. Examples of prodrugs include esters of hydroxy functional groups in compounds of formula I (eg acetate, formate and benzoate derivatives), carbamates (eg N, N-dimethylaminocarbonyl), amino N-acyl derivatives of functional groups (eg N-acetyl), N-mannich bases, Schiff bases and enaminones, ketones of compounds of formula I and oximes of aldehyde functional groups, acetals, ketals and enol esters, etc. The present invention is not limited to these (see Bundegaard, H. “Design of Prodrugs” p1-92, Elesevier, New York-Oxford (1985), etc.).

  “Protecting group” or “protecting group” refers in the sense conventionally associated with it in synthetic chemistry, where one reactive site in a polyfunctional compound is selected selectively by another unprotected reactive site. A group that selectively blocks so that it can be carried out. Certain methods of the present invention rely on protecting groups that block reactive nitrogen and / or oxygen atoms present in the reactants. For example, the terms “amino protecting group” and “nitrogen protecting group” are used interchangeably herein to refer to an organic group intended to protect a nitrogen atom against undesired reactions during the synthesis process. Point to. Exemplary nitrogen protecting groups include trifluoroacetyl, acetamide, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl ( BOC) and the like, but is not limited to these. Those skilled in the art know how to select groups for ease of removal and ability to withstand subsequent reactions.

“Solvate” means a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap solvent molecules in a crystalline solid state at a fixed molar ratio, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules and one of the substances, where the water maintains its molecular state in H ₂ O, and such combination results in one or more hydration. Things can be formed.

  “Subject” means mammals and non-mammals. Mammals are humans; non-human primates such as chimpanzees and other apes and monkeys; domestic animals such as cows, horses, sheep, goats, and pigs; companion animals such as rabbits, dogs, and cats; rats, mice, And any member of a mammal including, but not limited to, laboratory animals including rodents such as guinea pigs. Examples of non-mammals include, but are not limited to, birds. The term “subject” does not denote a particular age or sex.

“Treat” a disease state and “treatment” of a disease state are:
(I) preventing a disease state, i.e., in a subject who may be exposed to or susceptible to a disease state but has not yet experienced or represented symptoms of the disease state; Prevent clinical symptoms from occurring,
(Ii) inhibiting the disease state, ie preventing the progression of the disease state or its clinical symptoms, or (iii) alleviating the disease state, ie, causing the disease state or its clinical symptoms to be temporary or permanent Including retreating.

  The terms “treating”, “contacting” and “reacting”, when referring to chemical reactions, add or mix two or more reagents under appropriate conditions, as indicated and / or desired It means producing a product. The reaction that produces the indicated and / or desired product may not be obtained directly from the combination of the two reagents added initially, ie, the final indicated and / or desired product. One or more intermediates may be produced in the mixture, leading to the formation of

Nomenclature and Structure In general, the nomenclature used in this application is based on AUTONOM ™ v.4.0, a Beilstein Institute computer processing system for creating IUPAC systematic nomenclature. The chemical structure shown herein was created using ISIS® version 2.2.

  Open valences appearing on carbon, oxygen, sulfur or nitrogen atoms in the structures herein suggest the presence of hydrogen atoms.

Compounds One embodiment of the invention is a compound of formula I:

［式中：
ｍは、０〜４であり；
ｎは、０〜２であり；
Ａｒは、場合により置換されているアリール又は場合により置換されているヘテロアリールであり；
Ｒ^１は：
水素；
Ｃ_１−６−アルキル；
ヘテロ−Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｐ−Ｘ−（ＣＨ_２）_ｑ−Ｒ^ａであり；
ここで、
Ｘは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
ｐ及びｑは、それぞれ独立に０又は１であり；そして
Ｒ^ａは：
Ｃ_１−６アルキル；
Ｃ_１−６アルコキシ；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
ヒドロキシ；
アミノ；
Ｎ−Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
それぞれのＲ^２は、独立に：
ハロ；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６−アルキル；
シアノ；
ニトロ；
アミノ；
Ｎ−Ｃ_１−６アルキル−アミノ；
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ；又は
−（ＣＨ_２）_ｒ−Ｙ−（ＣＨ_２）_ｓ−Ｚ−（ＣＨ_２）_ｔ−Ｑ−（ＣＨ_２）_ｕ−Ｒ^ｂであり；
ここで、
ｒ、ｓ、ｔ及びｕは、それぞれ独立に０又は１であり；
Ｚは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
Ｘ及びＹは、それぞれ独立に−Ｏ−、−ＮＲ^ｃ−又は結合であり；
Ｒ^ｂは：
水素；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６アルキル；
シアノ；
アミノ；
Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
Ｒ^ｃは：
水素；又は
Ｃ_１−６アルキルである］で示される化合物又はその薬学的に許容しうる塩に関する。

[Where:
m is 0-4;
n is 0-2;
Ar is optionally substituted aryl or optionally substituted heteroaryl;
R ¹ is:
hydrogen;
Ci- ₆ -alkyl;
Hetero-C _1-6 alkyl; or — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a ;
here,
X is —C (O) — or —SO ₂ —;
p and q are each independently 0 or 1; and R ^a is:
C _1-6 alkyl;
C _1-6 alkoxy;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
Hydroxy;
amino;
N—C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and each R ² is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero- _Ci-6 -alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 alkyl-amino;
N, N-di-C _1-6 alkylamino; or — (CH ₂ ) _r —Y— (CH ₂ ) _s —Z— (CH ₂ ) _t —Q— (CH ₂ ) _u —R ^b ;
here,
r, s, t and u are each independently 0 or 1;
Z is —C (O) — or —SO ₂ —;
X and Y are each independently —O—, —NR ^c —, or a bond;
R ^b is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ^c is:
Is hydrogen or C _1-6 alkyl] or a pharmaceutically acceptable salt thereof.

  The scope of the present invention encompasses not only any isomers that may exist, but also mixtures of any isomers that may be formed. Furthermore, the scope of the present invention also encompasses solvates, salts and prodrugs of the subject compounds.

  In certain embodiments of formula I, n is 0.

  In certain embodiments of formula I, n is 1.

  In certain embodiments of formula I, n is 2.

  In certain embodiments of formula I, Ar is phenyl, indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl, or benzoimidazolyl, each as generally and specifically described herein. Substituted as described.

In certain embodiments of formula I, Ar is phenyl, indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl, or benzoimidazolyl, each optionally halo, C _1-6 alkyl, halo- C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N— Di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d, where w is 0 or 1; x is 0 to 2, ^{R d} is _{hydrogen, C 1-6} alkyl, halo _{-C 1-6} alkyl, hydroxy, heteroalkyl _{-C 1-6} alkyl, _{amino, C 1-6} alkyl - amino, or N, substituted by 1, 2 or 3 substituents selected from a a) N- di _{-C 1-6} alkylamino. Preferred optional substituents are halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N —Di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d, where w is 0 or 1 , X is 0-2 and R ^d is C _1-6 alkyl, halo-C _1-6 alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkyl. Is amino).

  In certain embodiments of formula I, Ar is aryl.

  In certain embodiments of formula I, Ar is optionally substituted phenyl.

In certain embodiments of formula I, Ar is optionally halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N-di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH _{2) w -S (O) x} -R d ( where, w is 0 or 1, x is 0 to 2, ^{R d} is _{hydrogen, C 1-6} alkyl, halo -C _{1 -6} alkyl, hydroxy, heteroalkyl _{-C 1-6} alkyl, _{amino, C 1-6} alkyl - amino, or N, 1, 2 or 3 is selected from a a) N- di _{-C 1-6} alkylamino It is phenyl substituted by the substituent of Preferred optional substituents are halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N —Di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d, where w is 0 or 1 , X is 0-2 and R ^d is C _1-6 alkyl, halo-C _1-6 alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkyl. Is amino).

In certain embodiments of formula I, Ar is optionally halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxy, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N-di-C _1-6 alkylamino, or — (CH ₂ ) _w —S (O) _x —R ^d (Wherein w is 0 or 1, x is 0-2, and R ^d is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, hetero-C _{1- 6} alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino).

In certain embodiments of formula I, Ar is optionally halo, C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfanyl, cyano, hydroxy, nitro, amino, or C _1-6. Substituted once, twice or three times by alkyl, C _1-6 alkylsulfinyl, —C (O) —C _1-6 alkyl, N—C _1-6 alkyl-amino, or halo-C _1-6 alkyl Is phenyl.

In certain embodiments of formula I, Ar is phenyl optionally substituted once or twice by halo, C _1-6 alkyl, C _1-6 alkoxy, cyano or hydroxy.

In certain embodiments of formula I, Ar is phenyl substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, cyano or hydroxy.

  In certain embodiments of formula I, Ar is heteroaryl.

  In certain embodiments of formula I, Ar is heteroaryl selected from indolyl, indazolyl, benzimidazolyl, pyridyl, pyrimidinyl, dihydroindolonyl, quinolinyl, and pyrrolyl, each optionally substituted.

In certain embodiments of formula I, Ar is indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl, or benzoimidazolyl, each optionally halo, C _1-6 alkyl, halo-C _{1 -6} alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro, amino, N-C _1-6 alkyl-amino, N, N-di- C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d, where w is 0 or 1, and x is is 0 to 2, ^{R d} is _{hydrogen, C 1-6} alkyl, halo _{-C 1-6} alkyl, hydroxy, heteroalkyl _{-C 1-6} alkyl, _{amino, C 1-6} alkyl - amino Or N, _N-di--C a _1-6 alkylamino) is selected from 1, 2 or 3, preferably substituted by 1 or 2 optional substituents. Preferred optional substituents are halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N —Di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d, where w is 0 or 1 , X is 0-2 and R ^d is C _1-6 alkyl, halo-C _1-6 alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkyl. Is amino). Further preferred optional substituents are halo, C _1-6 alkyl, C _1-6 alkoxy, cyano or hydroxy.

In certain embodiments of formula I, Ar is heteroaryl selected from indolyl, indazolyl, benzimidazolyl, pyridyl, pyrimidinyl, dihydroindolonyl, quinolinyl and pyrrolyl, each optionally halo, C _1-6 alkyl , Halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxy, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _1-6 alkyl-amino, N , N- Ji _{-C 1-6} alkylamino, or _{- (CH 2) w -S (} O) x -R d ( where, w is 0 or 1, x is 0-2, and ^{R d} is _{hydrogen, C 1-6} alkyl, halo _{-C 1-6} alkyl, hydroxy, heteroalkyl _{-C 1-6} alkyl, _{amino, C 1-6} alkyl - amino, Is N, substituted once or twice with any of the a) N- Ji _{-C 1-6} alkylamino.

In certain embodiments of formula I, Ar is indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl and dihydroindolonyl, each optionally halo, C _1-6 alkyl, C _1-6 alkoxy, cyano Or substituted once or twice by either hydroxy.

In certain embodiments of formula I, Ar is indolyl or indazolyl, each optionally substituted once with hydroxy, halo, or C _1-6 alkyl.

  In certain embodiments of formula I, Ar is optionally substituted indolyl.

  In certain embodiments of formula I, Ar is optionally substituted indazolyl.

  In certain embodiments of formula I, Ar is optionally substituted indol-3-yl.

  In certain embodiments of formula I, Ar is optionally substituted indol-5-yl.

  In certain embodiments of formula I, Ar is optionally substituted indazol-3-yl.

  In certain embodiments of formula I, Ar is optionally substituted indazol-5-yl.

In certain embodiments of formula I, R ¹ is hydrogen, C _1-6 alkyl, hetero-C _1-6 alkyl, or — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a where , X is —C (O) — or —SO ₂ —, p and q are each independently 0 or 1, and R ^a is C _1-6 alkyl, C _1-6 alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy, hydroxyl, amino, N-C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino).

In certain embodiments of formula I, R ¹ is hydrogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, or — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a where , X is —C (O) — or —SO ₂ —, p and q are each independently 0 or 1, and R ^a is C _1-6 alkyl, C _1-6 alkoxy, halo -C _1-6 alkyl, halo-C _1-6 alkoxy, hydroxyl, amino, N-C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino).

In certain embodiments of formula I, R ¹ is hydrogen or C _1-6 alkyl.

  In certain embodiments of formula I, m is 0 or 1.

In certain embodiments of formula I, R ² is halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxy; hetero-C _{1- 6} -alkyl, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N-di-C _1-6 alkylamino, hydroxy-C _1-6 alkoxy, —O—C (O) —CH (NH ₂ ) C _1-6 alkyl, or — (CH ₂ ) _r —Y— (CH ₂ ) _s —Z— (CH ₂ ) _t —Q— (CH ₂ ) _u —R ^b (where r, s, t and u are each independently 0 or 1, Y and Q are each independently —O—, —NR ^c — or a bond, and Z is —C (O) — or —SO _2. - and, ^{R b} is _{hydrogen, C 1-6} alkyl, halo _{-C 1-6} alkyl, halo C _{1-6 alkoxy, C 1-6} alkoxy, hydroxy, heteroalkyl _{-C 1-6} alkyl, cyano, _{amino, C 1-6} alkyl - amino, or N, a N- di _{-C 1-6} alkylamino, And R ^c is hydrogen or C _1-6 alkyl).

In certain embodiments of formula I, ^{R 2} is _{halo, C 1-6 alkyl, C 1-6} alkoxy, hydroxy; hydroxy _{-C 1-6} alkyl, cyano, hydroxy _{-C 1-6} alkoxy, -O- C (O) —CH (NH ₂ ) C _1-6 alkyl, or — (CH ₂ ) _r —Y— (CH ₂ ) _s —Z— (CH ₂ ) _t —Q— (CH ₂ ) _u —R ^b (Where r, s, t and u are each independently 0 or 1, Y and Q are each independently —O—, —NR ^c — or a bond, and Z is —C (O )-Or —SO ₂ —, and R ^b is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, amino, C _1-6 alkyl-amino, or N, N-di-C. _1-6 alkylamino and R ^c is hydrogen or C _1-6 alkyl ).

In certain embodiments of formula I, R ² is C _1-6 alkyl, C _1-6 alkoxy, hydroxy, halo, or cyano.

In certain embodiments of formula I, R ² is halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkoxy, hydroxy-C _1-6 alkyl, cyano, —O—. C (O) —R ^b , —O—CH ₂ —C (O) —R ^b , —C (O) —R ^b or —CH ₂ —C (O) —R ^b , —O—C (O) CH (NH ₂ ) C _1-6 alkyl, —CH ₂ —OC (O) —R ^b , or —O—S (O) ₂ —R ^b .

In certain embodiments of formula I, R ^b is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxy, hetero-C _{1- 6} alkyl, cyano, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino.

In certain embodiments of formula I, R ^b is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, amino, C _1-6 alkyl-amino, or N, N-di-C _{1. -6} alkylamino and R ^c is hydrogen or C _1-6 alkyl.

In certain embodiments of formula I, R ² is halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkoxy, hydroxy-C _1-6 alkyl, cyano, —O—. C (O) —R ^b , —O—CH ₂ —C (O) —R ^b , —C (O) —R ^b or —CH ₂ —C (O) —R ^b .

In certain embodiments of formula I, R ¹ is — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a .

In certain embodiments of formula I, R ¹ is —CH ₂ —C (O) —R ^a .

In certain embodiments of formula I, R ¹ is —C (O) —R ^a .

In certain embodiments of formula I, R ¹ is —SO ₂ —R ^a .

  In certain embodiments of formula I, n is 2 and Ar is optionally substituted phenyl.

  In certain embodiments of formula I, n is 2, Ar is optionally substituted phenyl, and m is 0 or 1.

In certain embodiments of formula I, n is 2, Ar is optionally substituted phenyl, m is 0 or 1, and R ² is C _1-6 alkyl, C _1-6 alkoxy, hydroxy, halo or cyano.

In certain embodiments of formula I, n is 2, Ar is optionally substituted phenyl, m is 0 or 1, and R ² is C _1-6 alkyl, C _{1- 6} alkoxy, hydroxy, halo or cyano, and R ¹ is hydrogen or C _1-6 alkyl.

  In certain embodiments of the invention, the subject compound has the formula I:

［式中、
ｍは、０〜４であり、好ましくは０、１、２であり；
ｎは、０〜２であり；
Ａｒは、フェニル、インドリル、インダゾリル、キノリニル、ピロリル、ピリジニル、ピリミジニル、ジヒドロインドロニル又はベンゾイミダゾリルであり、場合により、
ハロ；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
Ｃ_１−６アルコキシ；
ヒドロキシ；
シアノ；
ニトロ；
アミノ；
Ｎ−Ｃ_１−６−アルキル−アミノ；
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ；
−Ｃ（Ｏ）−Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｗ−Ｓ（Ｏ）_ｘ−Ｒ^ｄ
から選択される１、２又は３個の置換基によって置換されており；
ここで：
ｗは、０又は１であり；
ｘは、０〜２であり；
Ｒ^ｄは：
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
アミノ；
Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
Ｒ^１は：
水素；
Ｃ_１−６−アルキル；
ヒドロキシアルキル；
−（ＣＨ_２）_ｐ−Ｘ−（ＣＨ_２）_ｑ−Ｒ^ａであり；
ここで、
Ｘは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
ｐ及びｑは、それぞれ独立に０又は１であり；そして
Ｒ^ａは：
Ｃ_１−６アルキル；
Ｃ_１−６アルコキシ；
ヒドロキシ；
アミノ；
Ｎ−Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
それぞれのＲ^２は、独立に：
ハロ；
Ｃ_１−６アルキル；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヒドロキシアルキル；
シアノ；
ヒドロキシ−Ｃ_１−６アルコキシ；
−Ｏ−Ｃ（Ｏ）−ＣＨ（ＮＨ_２）Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｒ−Ｙ−（ＣＨ_２）_ｓ−Ｚ−（ＣＨ_２）_ｔ−Ｑ−（ＣＨ_２）_ｕ−Ｒ^ｂであり；
ここで、
ｒ、ｓ、ｔ及びｕは、それぞれ独立に０又は１であり；
Ｙ及びＱは、それぞれ独立に−Ｏ−、−ＮＲ^ｃ−又は結合であり；
Ｚは、−Ｃ（Ｏ）−又は−ＳＯ_２−であり；
Ｒ^ｂは：
水素；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ヒドロキシ；
アミノ；
Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
Ｒ^ｃは：
水素；又は
Ｃ_１−６アルキルである］で示される化合物又はその薬学的に許容しうる塩である。

[Where:
m is 0-4, preferably 0, 1, 2;
n is 0-2;
Ar is phenyl, indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl or benzoimidazolyl, optionally
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
C _1-6 alkoxy;
Hydroxy;
Cyano;
Nitro;
amino;
N—C _1-6 -alkyl-amino;
N, N-di-C _1-6 alkylamino;
-C _{(O) -C 1-6} alkyl; or _{- (CH 2) w -S (} O) x -R d
Substituted by 1, 2 or 3 substituents selected from:
here:
w is 0 or 1;
x is 0-2;
R ^d is:
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ¹ is:
hydrogen;
Ci- ₆ -alkyl;
Hydroxyalkyl;
- _{(CH 2)} be a _{p -X- (CH 2) q -R} a;
here,
X is —C (O) — or —SO ₂ —;
p and q are each independently 0 or 1; and R ^a is:
C _1-6 alkyl;
C _1-6 alkoxy;
Hydroxy;
amino;
N—C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and each R ² is independently:
Halo;
C _1-6 alkyl;
C _1-6 alkoxy;
Hydroxy;
Hydroxyalkyl;
Cyano;
Hydroxy-C _1-6 alkoxy;
_{-O-C (O) -CH (} NH 2) C 1-6 alkyl; or _{- (CH 2) r -Y- (} CH 2) s -Z- (CH 2) t -Q- (CH 2) u It is a -R ^b;
here,
r, s, t and u are each independently 0 or 1;
Y and Q are each independently —O—, —NR ^c — or a bond;
Z is —C (O) — or —SO ₂ —;
R ^b is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Hydroxy;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ^c is:
Hydrogen; or a C _1-6 alkyl as] a compound represented by or a pharmaceutically acceptable salt thereof.

  In certain embodiments of the invention, the subject compound has the formula II:

［式中：
ｖは、０〜４であり；
それぞれのＲ^３は、独立に：
ハロ；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６アルキル；
シアノ；
ニトロ；
アミノ；
Ｎ−Ｃ_１−６−アルキル−アミノ；
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ；
−Ｃ（Ｏ）−Ｃ_１−６アルキル；又は
−（ＣＨ_２）_ｗ−Ｓ（Ｏ）_ｘ−Ｒ^ｄであり；
ここで：
ｗは、０又は１であり；
ｘは、０〜２であり；
Ｒ^ｄは：
水素；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ヒドロキシ；
ヘテロ−Ｃ_１−６アルキル；
アミノ；
Ｃ_１−６アルキル−アミノ；又は
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノであり；そして
Ｒ^１及びＲ^２は、本明細書で定義したとおりである］で示される化合物である。

[Where:
v is 0-4;
Each R ³ is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 -alkyl-amino;
N, N-di-C _1-6 alkylamino;
-C _{(O) -C 1-6} alkyl; or _{- (CH} 2) be ^{_{w -S (O) x -R d}} ;
here:
w is 0 or 1;
x is 0-2;
R ^d is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Hydroxy;
Hetero-C _1-6 alkyl;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ¹ and R ² are as defined herein].

  In certain embodiments of formula II of the invention, v is 1-4.

  In certain embodiments of formula II, v is 0, 1, 2, or 3.

In certain embodiments of Formula II, ^{R 3,} _{halo, C 1-6} alkyl, halo _{-C 1-6} alkyl, halo _{-C 1-6 alkoxy, C 1-6} alkoxy, hydroxyl, heteroaryl _{-C 1- 6} alkyl, cyano, nitro, amino, N—C _1-6 -alkyl-amino, N, N-di-C _1-6 alkylamino, or — (CH ₂ ) _w —S (O) _x —R ^d ( Here, w is 0 or 1, x is 0 to 2, R ^d is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxyl, hetero-C _1-6 alkyl , _{amino, C 1-6} alkyl - amino, or N, N- di _{-C 1-6} alkylamino).

In embodiments of formula II, R ¹ and R ² are as defined in the embodiments described for formula I.

  In certain embodiments, the compound has Formula IIa or Formula IIb:

［式中、ｖ、Ｒ^１、Ｒ^２及びＲ^３は、本明細書で定義したとおりであり、特には、式ＩＩについて定義したとおりである］で示される化合物であってもよい。

[Wherein v, R ¹ , R ² and R ³ are as defined herein, and in particular, as defined for Formula II].

In certain embodiments of formula II, formula IIa, or formula IIb, R ¹ is hydrogen or C _1-6 alkyl.

In certain embodiments of formula II, formula IIa, or formula IIb, R ² is C _1-6 alkyl, C _1-6 alkoxy, hydroxy, halo, or cyano.

In certain embodiments of formula II, formula IIa, or formula IIb, R ² is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, halo Or cyano.

In certain embodiments of formula II, formula IIa or formula IIb, R ² is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, halo or cyano It is.

Formula II, in certain embodiments of formula IIa or formula IIb, ^{R 3} is _{C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6} alkylsulfonyl, hydroxy, halo or cyano It is.

In certain embodiments of formula II, formula IIa, or formula IIb, R ² is halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkoxy, hydroxy-C _1-6 alkyl , Cyano, —O—C (O) —R ^b , —O—CH ₂ —C (O) —R ^b , —C (O) —R ^b or —CH ₂ —C (O) —R ^b . .

In certain embodiments of formula II, formula IIa, or formula IIb, v is 0, 1 or 2, and R ² and R ³ are each independently C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, halo or cyano, and R ¹ is hydrogen or C _1-6 alkyl.

  In certain embodiments of the invention, the compound has the formula III:

［式中、Ａｒは、インドリル、インダゾリル、キノリニル、ピロリル、ピリジニル、ピリミジニル、ジヒドロインドロニル又はベンゾイミダゾリルであり、それらの各々は場合により１又は２個の置換基によって置換されており、好ましくは、ハロ、Ｃ_１−６アルキル、ハロ−Ｃ_１−６アルキル、ハロ−Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシ、ヒドロキシル、ヘテロ−Ｃ_１−６アルキル、シアノ、ニトロ、アミノ、Ｎ−Ｃ_１−６アルキル−アミノ、Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ、−Ｃ（Ｏ）−Ｃ_１−６アルキル、又は−（ＣＨ_２）_ｗ−Ｓ（Ｏ）_ｘ−Ｒ^ｄ（ここで、ｗは、０又は１であり、ｘは、０〜２であり、Ｒ^ｄは、水素、Ｃ_１−６アルキル、ハロ−Ｃ_１−６アルキル、ヒドロキシ、ヘテロ−Ｃ_１−６アルキル、アミノ、Ｃ_１−６アルキル−アミノ、又はＮ，Ｎ−ジ−Ｃ_１−６アルキルアミノである）から選択される１個の任意の置換基によって置換されており；そして、Ｒ^１及びＲ^２は、式Ｉ、ＩＩ、ＩＩａ又はＩＩｂで記載したとおりである］で示される化合物である。

[Wherein Ar is indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl or benzoimidazolyl, each of which is optionally substituted by one or two substituents, preferably Halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _{1 −6} alkyl-amino, N, N-di-C _1-6 alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d (where , w is 0 or 1, x is 0 to 2, ^{R d} is _{hydrogen, C 1-6} alkyl, halo _{-C 1-6} alkyl, hydroxy, heteroalkyl _{-C 1-6} alkyl _{Amino, C 1-6} alkyl - amino, or N, is substituted by one of the optional substituents selected from a) N- di _{-C 1-6} alkylamino; and, ^{R 1} and ^{R 2} Is as described in formula I, II, IIa or IIb].

Preferred optional substituents for Ar in formula III are halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl. - amino, N, N-di _{-C 1-6} alkylamino, -C _{(O) -C 1-6} alkyl, or _{- (CH 2) w -S (} O) x -R d ( where, w is , 0 or 1, x is 0 to 2, and R ^d is C _1-6 alkyl, halo-C _1-6 alkyl, amino, C _1-6 alkyl-amino, or N, N-di. -C _1-6 alkylamino).

Further preferred optional substituents for Ar in formula III are halo, C _1-6 alkyl or hydroxy.

  Preferred Ars of formula III are indolyl and indazolyl, each optionally substituted by one substituent as described in formula III.

  More preferred Ar of formula III is 5-indolyl, 3-indolyl or 5-indazolyl, each optionally substituted by one substituent as described in formula III.

  In certain embodiments of the invention, the compound has the formula IV:

［式中：
Ａは、Ｃ又はＮであり；
Ｒ^４は：
水素；又は
Ｃ_１−６アルキルであり；
Ｒ^５及びＲ^６は、それぞれ独立に：
ハロ；
Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルキル；
ハロ−Ｃ_１−６アルコキシ；
Ｃ_１−６アルコキシ；
ヒドロキシ；
ヘテロ−Ｃ_１−６アルキル；
シアノ；
ニトロ；
アミノ；
Ｃ_１−６アルキル−アミノ；
Ｎ，Ｎ−ジ−Ｃ_１−６アルキルアミノ；
−（ＣＨ_２）ｗ−Ｓ（Ｏ）_ｘ−Ｒ^ｄ；であり、そして
ｗ、ｘ、Ｒ^１、Ｒ^２及びＲ^ｄは、上記で定義したとおりである］で示される化合物であってもよい。

[Where:
A is C or N;
R ⁴ is:
Hydrogen; or C _1-6 alkyl;
R ⁵ and R ⁶ are each independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
Nitro;
amino;
C _1-6 alkyl-amino;
N, N-di-C _1-6 alkylamino;
_{- (CH 2) w-S} (O) x -R d; a, and ^{w, x, R 1, R} 2 and ^{R d} may be a compound represented by the is] as defined above Good.

If any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^a , R ^b , R ^c and R ^d is alkyl or contains an alkyl moiety, such The alkyl is preferably lower alkyl, ie C ₁ -C ₆ alkyl, more preferably C ₁ -C ₄ alkyl.

  Representative and preferred compounds of the present invention are shown in Table 1.

Synthesis The compounds of the present invention can be prepared by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.

  Starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or by methods known to those skilled in the art by Fieser and Fieser's. Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991 , Volumes 1-40, and can be prepared according to procedures specified in references. The following synthetic reaction schemes are merely illustrative of some of the ways in which the compounds of the present invention can be synthesized, and any modifications can be made to these synthetic reaction schemes, with reference to the disclosure contained in this application. It is suggested to the contractor.

  Starting materials and intermediates in synthetic reaction schemes can be isolated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc., if desired. Such materials can be characterized by conventional means, including physical constants and spectral data.

  Unless specified to the contrary, the reactions described herein are preferably conducted at a reaction temperature in the range of about −78 to about 150 ° C. at atmospheric pressure, more preferably about 0 to about 0 ° C., under an inert atmosphere. It is carried out at about 125 ° C and most preferably conveniently at about room temperature (or ambient temperature), for example about 20 ° C.

Scheme A below illustrates one synthetic procedure useful for preparing the compounds of the present invention, where R is lower alkyl, PG is an amine protecting group, and Ar, m and R ² is as defined in this specification.

In Step 1 of Scheme A, bromobenzoic acid compound a is reduced to bromobenzyl alcohol b . This reduction may be performed using, for example, a boron reducing agent. In step 2, compound b is treated with methanesulfonyl chloride to form mesyl ester compound c . Cyanation is carried out in step 3 by treating compound c with a cyanate reactant, such as tetraalkylammonium cyanate, to obtain nitrile compound d . Compound d is then alkylated in step 4 by treatment with a base such as lithium aluminum hydride followed by treatment with 2-bromoacetate to give nitrile ester compound e . Compound e is reduced in step 5 to give nitrile alcohol compound f . In Step 6, the nitrile group of compound f is reduced and protected to give amino alcohol compound g . In step 7, compound g is treated with methanesulfonyl chloride to form mesyl ester compound h . Compound h is then subjected to cyclization in step 8 to give phenylpyrrolidine compound i . Cyclization can be achieved, for example, by treating compound h with potassium bis (trimethylsilyl) amide. In step 9, compound i is reacted with aryl thiol j under Buchwald conditions in the presence of a palladium catalyst to give bromopyrrolidone thioether k . In step 10, the sulfur atom of compound k can be oxidized with an oxidizing agent such as peracid to obtain arylsulfonylphenylpyrrolidine compound m . Compound m can be deprotected in step 11 to give compound n , which is a compound of formula I of the present invention.

  All variations in the procedure of Scheme A are possible and are suggested to one skilled in the art. Specific details for preparing the compounds of the invention are described in the Examples section below.

Utility The compounds of the present invention have selective affinity for 5-HT receptors, including 5-HT ₆ , 5-HT _2A receptors, or both, and Parkinson's disease, Huntington's disease, anxiety, depression, Manic depression, psychosis, epilepsy, obsessive-compulsive disorder, mood disorder, migraine, Alzheimer's disease (enhanced cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic attacks, akathisia Attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, certain CNS disorders such as schizophrenia, and spinal trauma and / or It is expected to be useful in the treatment of disorders associated with head trauma, such as hydrocephalus. Such compounds are also expected to be useful in the treatment of certain GI (gastrointestinal) disorders, such as bowel dysfunction and irritable bowel syndrome.

Testing The pharmacology of the compounds of the present invention was determined by procedures recognized in the art. In vitro techniques for determining the affinity of test compounds at the 5-HT6 and 5-HT2A receptors by radioligand binding and functional assays are described below.

Administration and Pharmaceutical Compositions The present invention comprises at least one compound of the present invention, or individual isomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. A pharmaceutically acceptable carrier, and optionally a pharmaceutical composition, optionally with other therapeutic and / or prophylactic ingredients.

  In general, the compounds of this invention are administered in any therapeutically effective amount and with any accepted method of administration for drugs that serve a similar utility. Suitable dosage ranges are typically 1-500 mg per day, preferably 1-100 mg per day, and most preferably 1-30 mg per day, the severity of the disease being treated, the age of the subject And a number of factors such as the relative health, the efficacy of the compound used, the route and form of administration, the indication for which the application is intended, and the choice and experience of the physician involved. Those skilled in the art of treating such diseases will be able to therapeutically treat the compounds of the present invention against a given disease without undue trial and error and by relying on personal knowledge and disclosure of the present application. An effective amount can be determined.

  The compounds of the invention are administered orally (including buccal and sublingual), rectal, intranasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intraspinal, subcutaneous and intravenous). It may be administered as a pharmaceutical formulation including those suitable for or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral and uses a conventional daily dosage regimen that can be adjusted according to the degree of affliction.

  The compounds of the present invention may be in the form of pharmaceutical compositions and unit doses together with one or more conventional adjuvants, carriers, or diluents. The pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, the unit dosage form being within the intended range of daily doses used. Any suitable effective amount of the corresponding active ingredient can be included. The pharmaceutical composition may be a solid such as a tablet or filled capsule, semi-solid, powder, sustained release formulation, or a liquid such as a solution, suspension, emulsion, elixir or oral filled capsule. Or in the form of a suppository for rectal or vaginal administration; or in the form of a sterile liquid for injection for parenteral use. Thus, formulations containing about 1 mg of active ingredient per tablet, more broadly about 0.01 to about 100 mg are suitable representative unit dosage forms.

  The compounds of the present invention can be formulated in a wide variety of oral dosage forms. The pharmaceutical compositions and dosage forms can contain as active ingredient one or more compounds of the invention, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier is one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. It's okay. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active ingredient is generally mixed with the carrier having the required binding capacity in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain from about 1 to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Not. The term “formulation” includes a formulation of an active compound with an encapsulating material as a carrier that provides a capsule in which an active ingredient with or without a carrier is surrounded by a carrier associated therewith. Is intended. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

  Other forms suitable for oral administration are intended to be converted into liquid form preparations such as emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or liquid form preparations just prior to use. Solid form preparations are included. Emulsions can be prepared in solution, for example, an aqueous propylene glycol solution, or can contain emulsifiers such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions and emulsions, in addition to active ingredients, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers. Etc. can be contained.

  The compounds of the present invention can be formulated for parenteral administration (eg, by injection, eg, by bolus injection or continuous infusion), ampules with preservatives, pre-filled syringes (pre -filled syringes), small infusion containers or multi-dose containers can be present in unit dosage form. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, such as a solution in an aqueous polyethylene glycol solution. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate), preservatives, wetting Formulations such as agents, emulsifiers or suspensions, stabilizers and / or dispersants may be included. Alternatively, the active ingredient is in powder form, obtained by aseptic separation of a sterilized solid or by lyophilization from a constituent solution prior to use using a suitable vehicle, such as sterilized, pyrogen-free water. It may be.

  The compounds of the present invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. For example, ointments and creams can be formulated with aqueous or oily bases with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active agent in flavored bases, usually sucrose and acacia or tragacanth; in inert bases such as gelatin and glycerin or sucrose and acacia. Pastel agents containing the active ingredient; as well as mouthwashes containing the active ingredient in a suitable liquid carrier.

  The compounds of the present invention can be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The homogeneous molten mixture is then poured into convenient sized molds, allowed to cool and solidify.

  The compounds of the present invention can be formulated for vaginal administration. In addition to the active ingredient, pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers are known in the art.

  The subject compounds may be formulated for nasal administration. Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a drop bottle, pipette or spray. The formulation can be provided in a single dose or multiple dose form. In the case of the latter drop bottle or pipette, this can be achieved by the patient administering an appropriate and predetermined volume of solution or suspension. In the case of a spray, this can be achieved, for example, using a metering atomizing spray pump.

  The compounds of the invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound generally has a small particle size, for example on the order of 5 μm or less. Such a particle size can be obtained by methods known in the art, such as pulverization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The Aerosols are also surfactants such as lecithin and the active ingredients are in the form of dry powders, eg, suitable powders such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP) It can be provided as a powder mixture of the compounds in a base. The powder carrier will form a gel in the nasal cavity. The powder composition may be present in unit dosage form, such as a gelatin capsule or cartridge, or a blister pack, from which the powder is administered by inhaler.

  If desired, the formulation can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is required and compliance with the patient's treatment regime is important. Compounds in transdermal delivery systems are often bound to a skin-attached solid support. The compound of interest can also be combined with a penetration enhancer, such as an azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subcutaneous layer by surgery or infusion. Subcutaneous implants encapsulate the compound with a lipid-soluble membrane such as silicone rubber or a biodegradable polymer such as polyacetic acid.

  The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can itself be a capsule, tablet, cachet or lozenge, or any suitable number of these in package form.

  Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Exemplary pharmaceutical formulations containing the compounds of the present invention are described below.

Example

  The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but only as examples and representatives of the invention. The following abbreviations can be used in the examples.

List of Abbreviations AcOH Acetic acid n-BuLi n-Butyllithium (BOC) ₂ O Di-tert-Butyl dicarbonate Dichloromethane / methylene chloride DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide Ee Enantiomeric excess EtOAc Ethyl acetate HPLC High pressure liquid chromatography LAH Lithium aluminum hydride LDA Lithium diisopropylamide m-CPBA 3-chloroperoxybenzoic acid MeOH Methanol MsCl Methanesulfonyl chloride PdCl ₂ dppf 1,1-bis (diphenylphosphino) ferrocene dichloropa
Radium (II)
Pd ₂ (dba) ₃ Tris (dibenzylideneacetone) dipalladium (0)
KHMDS potassium bis (trimethylsilyl) amide TBAF tetrabutylammonium fluoride TEA triethylamine THF tetrahydrofuran TFA trifluoroacetic acid TLC thin layer chromatography Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethyl key
Santen

Preparation 1
3- (4-Bromo-2-methyl-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester The synthetic procedure described in this preparation was performed using the procedure in Scheme B.

Step 1 (4-Bromo-2-methyl-phenyl) -methanol BH ₃ (1M in THF, 720 mL, 0.7194 mol) was added to a solution of 4-bromo-2-methylbenzoic acid (51.57 g, 0.2398 mol). Was added slowly at 0 ° C. The ice bath was removed and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 ° C. and water was added slowly. The reaction mixture was then stirred at room temperature for 30 minutes. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with NaHCO ₃ (saturated solution), water and brine; dried over MgSO ₄ , filtered and evaporated under reduced pressure to give (4-bromo 2-Methyl-phenyl) -methanol was obtained and used directly in step 2 without further purification.

Step 2 Methanesulfonic acid 4-bromo-2-methyl-benzyl ester To a solution of (4-bromo-2-methyl-phenyl) -methanol (46.65 g, 0.2320 mol) in DCM (500 mL) was added mesyl chloride ( 20.65 mL, 0.2668 mol) was added at −15 ° C., followed by TEA (37.04 mL, 0.2668 mol). The reaction was stirred at −15 ° C. for 1.5 hours. Then a saturated solution of NH ₄ Cl was added at −15 ° C. and the resulting mixture was extracted with DCM. The organic phase was dried over MgSO _{4 ,} filtered and concentrated under reduced pressure to give methanesulfonic acid 4-bromo-2-methyl-benzyl ester as a white solid in quantitative yield (65 g) which was Used directly in step 3 without further purification.

Step 3 (4-Bromo-2-methyl-phenyl) -acetonitrile tetrabutylammonium cyanide (1.02 g, 3.799 mmol) was added to methanesulfonic acid 4-bromo-2-methyl-benzyl ester in THF (20 mL). To a solution of (1.01 g, 3.618 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, water was added to the residue and the mixture was extracted with Et ₂ O. The combined organic extracts were washed with water and brine; dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 9/1) to give 0.65 g (80% yield) of 4-bromo-2-methyl-phenyl) -acetonitrile as a white solid.

Step 4 3- (4-Bromo-2-methyl-phenyl) -3-cyano-propionic acid methyl ester lithium diisopropylamide (2M in THF, 110 mL) was added to (4-bromo-2-methyl in THF (400 mL). -Phenyl) -acetonitrile (38.55 g, 0.1835 mol) was added dropwise at -78 ° C. The reaction mixture was stirred for 10 minutes and methyl bromoacetate (16.87 mL, 0.1835 mol) was added. The resulting mixture was stirred at −78 ° C. for 2 hours. NH ₄ Cl saturated solution was then added at −78 ° C. and the resulting mixture was allowed to warm to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 9/1) to give 43.09 g of 3- (4-bromo-2-methyl-phenyl) -3-cyano-propionic acid methyl ester (83% yield). ) Was obtained as a yellow oil.

Step 5 2- (4-Bromo-2-methyl-phenyl) -4-hydroxy-butyronitrile lithium borohydride (4.99 g, 0.2290 mol) was added 3- (4-bromo-2 in THF (500 mL). -Methyl-phenyl) -3-cyano-propionic acid methyl ester (43.08 g, 0.1527 mol) was added to the room temperature solution and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0 ° C. and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added slowly until the pH reached 1-2. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 7/3) to give 27.3 g (87% yield) of 2- (4-bromo-2-methyl-phenyl) -4-hydroxy-butyronitrile. As a solid.

Step 6 2- (4-Bromo-2-methyl-phenyl)-in [2- (4-Bromo-2-methyl-phenyl) -4-hydroxy-butyl] -carbamic acid tert-butyl ester MeOH (750 mL) To a solution of 4-hydroxy-butyronitrile (27.3 g, 0.1074 mol) was added (BOC) ₂ O (46.9 g, 0.2149 mol) at 0 ° C., followed by NiCl ₂ . 6H ₂ O (2.55 g, 0.01074 mol) and sodium borohydride (27.83 g, 0.7359 mol) were added. The mixture was stirred at room temperature for 24 hours and diethylenetriamine (12 mL, 0.1074 mol) was added. The reaction mixture was stirred for 30 minutes and then the solvent was evaporated under reduced pressure. The resulting crude material was partitioned between NaHCO ₃ (10% aqueous solution) and EtOAc. The organic phase was washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 6/4) to give [2- (4-bromo-2-methyl-phenyl) -4-hydroxy-butyl] -carbamic acid tert-butyl ester. 3 g (yield 79%) was obtained.

Step 8 Methanesulfonic acid 3- (4-bromo-2-methyl-phenyl) -4-tert-butoxycarbonylamino-butyl ester mesyl chloride (7.53 mL, 0.09726 mol) was dissolved in [2] in DCM (600 mL). To a solution of-(4-bromo-2-methyl-phenyl) -4-hydroxy-butyl] -carbamic acid tert-butyl ester (30.3 g, 0.08457 mol) was added at -78 ° C followed by TEA (27 mL, 0.1945 mol) was added. The reaction mixture was stirred at −78 ° C. for 1 hour and then allowed to reach room temperature with stirring for an additional hour. A saturated aqueous NH ₄ Cl solution was added and the resulting mixture was extracted with DCM. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give methanesulfonic acid 3- (4-bromo-2-methyl-phenyl) -4-tert-butoxycarbonylamino-butyl ester. Was obtained and used without further purification.

Step 8 3- (4-Bromo-2-methyl-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester KHMDS (0.5 M in toluene, 186 mL, 0.09303 mol) dissolved in THF (400 mL) To the sulfonic acid 3- (4-bromo-2-methyl-phenyl) -4-tert-butoxycarbonylamino-butyl ester (36.9 g, 0.08457 mol) was added at 0 ° C. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. A saturated solution of NH ₄ Cl was added to the reaction mixture and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 8/2) to give 27.3 g of 3- (4-bromo-2-methyl-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (yield) 95%) was obtained as a clear oil.

  3- (4-Bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with 4-bromo-2-methoxybenzoic acid in place of 4-bromo-2-methylbenzoic acid in step 1. Were similarly prepared.

Preparation 2
3- (4-Mercapto-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester The synthetic procedure described in this preparation was performed according to the method shown in Scheme C.

Step 1 3- [2-Methoxy-4- (2-trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester tris (dibenzylideneacetone) dipalladium (0) (32 mg, 0 .03509 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (40 mg, 0.07017 mmol), 2- (triethylsilyl) ethanethiol (57 μL, 1.403 mmol) and DIPEA (0.257 mL). 2.807 mmol) of 3- (4-bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.403 mmol) in 1,4-dioxane (10 mL). To the solution. The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 95/5) to give 3- [2-methoxy-4- (2-trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert -0.380 g (66% yield) of butyl ester was obtained as a clear oil.

Step 2 A solution of 3- (4-mercapto-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester tetrabutylammonium fluoride (1.0 M in THF, 9.3 mL) was added to THF (5 mL). To a solution of 3- [2-methoxy-4- (2-trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (0.380 g, 0.9275 mmol) in The mixture was stirred at room temperature for 30 minutes. A solution of 10% KHSO ₄ / Na ₂ SO ₄ was added and the resulting mixture was extracted 3 times with EtOAc. The combined organic extracts were washed with water and brine; then dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography (hexane / EtOAc / AcOH, 80/20 / 0.1) to give 3- (4-mercapto-2-methoxy-phenyl) -pyrrolidine- 0.178 g (62% yield) of 1-carboxylic acid tert-butyl ester was obtained as a clear oil.

  3- (4-Bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was used in step 1 to give 3- (4-mercapto-2-methyl-phenyl) -pyrrolidine-1- Carboxylic acid tert-butyl ester was prepared similarly.

Preparation 3
1-Benzenesulfonyl-3-bromo-5-fluoro-1H-indole The synthetic procedure described in this preparation was performed according to the method shown in Scheme D.

Step 1 1-Benzenesulfonyl-5-fluoro-1H-indole KHMDS (0.5 M in toluene, 23 mL, 11.65 mmol) was added to 5-fluoroindole (1.5 g, 11.09 mmol) in DMF (23 mL). To the solution was added at 0 ° C. After stirring for 10 minutes, benzenesulfonyl chloride (1.55 mL, 12.209 mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 4 hours. A saturated solution of NH ₄ Cl was added to the reaction and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was recrystallized from toluene to give 2.26 g (74% yield) of 1-benzenesulfonyl-5-fluoro-1H-indole as a white solid.

Step 2 1-Benzenesulfonyl-3-bromo-5-fluoro-1H-indole bromine (0.187 mL, 3.632 mmol) was added to 1-benzenesulfonyl-5-fluoro-1H-indole (1 0.0 g, 3.632 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. A saturated solution of NH ₄ Cl was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 95/5) to give 0.676 g (53% yield) of 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole as a white solid. Obtained.

Preparation 4
3-Bromo-pyrrole-1-carboxylic acid tert-butyl ester The synthetic procedure described in this preparation was performed according to the method shown in Scheme E.

A solution of TBAF (1.0 M in THF, 3.6 mL) was added to a solution of 3-bromo-1-triisopropylsilanyl-1H-pyrrole (1.0 g, 3.308 mmol) in THF (10 mL), The mixture was stirred at room temperature for 30 minutes. (BOC) ₂ O (0.866 g, 3.965 mmol) and DMAP (40 mg, 0.3308 mmol) were added to the reaction and the resulting mixture was stirred for an additional 2 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc) to give 0.197 g (24% yield) of 3-bromo-pyrrole-1-carboxylic acid tert-butyl ester as a clear oil.

Preparation 5
4-Bromo-2-chloro-1- (4-methoxy-benzyloxy) -benzene The synthetic procedure described in this preparation was performed according to the method shown in Scheme F.

Potassium carbonate (0.98 g, 7.086 mmol) was added 4-bromo-2-chlorophenol (0.7 g, 3.374 mmol) and 4-methoxybenzyl bromide (0.51 mL, 3.543 mmol) in acetone (20 mL). ) And the mixture was stirred overnight at room temperature. The solid phase was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc and aqueous NaOH (2M). The organic layer was washed with water and brine; dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 99/1) to give 0.937 g (85% yield) of 4-bromo-2-chloro-1- (4-methoxy-benzyloxy) -benzene. Obtained as a yellow solid.

Preparation 6
(S) -3- (4-Bromo-2-hydroxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester The synthetic procedure described in this preparation was performed according to the method shown in Scheme G.

Step 1 A solution of NaOH (5.72 g, 143 mmol) in (4-bromo-2-methoxy-phenyl) -acetic acid water (29 mL) was added to (4-bromo-2-methoxy-phenyl) in MeOH (100 mL). -To a solution of acetonitrile (10.2 g, 45.1 mmol). The reaction mixture was heated to reflux for 18 hours. The solvent was evaporated under reduced pressure and water was added. The aqueous mixture was washed with diethyl ether and the aqueous layer was acidified to pH 1 by adding aqueous HCl (2M). The aqueous mixture was then extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give (4-bromo-2-methoxy-phenyl) -Acetic acid 9.49g (yield 86%) was obtained.

Step 2 (S) -3- [2- (4-Bromo-2-methoxy-phenyl) -acetyl] -4-isopropyl-oxazolidine-2-one triethylamine (0.66 mL, 4.75 mmol) was added to the first To a solution of (4-bromo-2-methoxy-phenyl) -acetic acid (1.02 g, 4.162 mmol) in THF (11 mL) in a round bottom flask was added under an argon atmosphere. The mixture was cooled at −78 ° C. and pivaloyl chloride (0.513 mL, 4.162 mmol) was added. After stirring at −78 ° C. for 10 minutes, the reaction mixture was warmed to 0 ° C., stirred for 30 minutes, and then cooled again at −78 ° C. (S) -4-Isopropyl-2-oxazolidinone (591.2 mg, 4.577 mmol) was dissolved in THF (20 mL) in a second round bottom flask, cooled to −78 ° C., and n-BuLi (2 in hexanes). 0.5M, 2.0 mL, 4.99 mmol) was added. After stirring at −78 ° C. for 10 minutes, the metallated oxazolidinone mixture in the second flask was added to the mixed anhydride in the first flask at −78 ° C. The reaction mixture was stirred at 0 ° C. for 4 hours and then at room temperature for 18 hours. NH ₄ Cl saturated solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 84/16) to give (S) -3- [2- (4-bromo-2-methoxy-phenyl) -acetyl] -4-isopropyl-oxazolidine- 1.13 g (77% yield) of 2-one was obtained.

Step 3 (S) -3- (4-Bromo-2-methoxy-phenyl) -4-((S) -4-isopropyl-2-oxo-oxazolidin-3-yl) -4-oxo-butyronitrile lithium diisopropylamide (2.0 M in heptane / THF / ethylbenzene, 1.58 mL, 3.16 mmol) was added to (S) -3- [2- (4-bromo-2-methoxy-phenyl) -acetyl] in THF (11 mL). To a solution of -4-isopropyl-oxazolidine-2-one (1.126 g, 3.16 mmol) was added at −78 ° C. under an argon atmosphere. The mixture was stirred for 15 minutes and bromoacetonitrile (0.23 mL, 3.32 mmol) was added at −78 ° C. The mixture was stirred for 3 hours at 0 ° C., followed by addition of a saturated solution of NH 4 _Cl. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 85/15) to give (S) -3- (4-bromo-2-methoxy-phenyl) -4-((S) -4-isopropyl-2. 755 mg (60% yield) of -oxo-oxazolidin-3-yl) -4-oxo-butyronitrile were obtained as a white solid.

Step 4 (S) -3- (4-Bromo-2-methoxy-phenyl) -4-hydroxy-butyronitrile A solution of sodium borohydride (389 mg) in water (1.82 mL) was added in THF (6 mL). (S) -3- (4-Bromo-2-methoxy-phenyl) -4-((S) -4-isopropyl-2-oxo-oxazolidine-3-yl) -4-oxo-butyronitrile (749 mg, 1. 895 mmol) solution under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C. and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was carefully added. After gas evolution ceased, the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 7/3) to give 470 mg (92% yield) of (S) -3- (4-bromo-2-methoxy-phenyl) -4-hydroxy-butyronitrile. Got.

Step 5 (S) -3- (4 in [(S) -3- (4-Bromo-2-methoxy-phenyl) -4-hydroxy-butyl] -carbamic acid tert-butyl ester MeOH (12.1 mL) - bromo-2-methoxy - phenyl) -4-hydroxy - butyronitrile (459 mg, to a solution of _{1.699mmol), (BOC) 2 O} (736.3mg, 3.398mmol), NiCl 2. 6H ₂ O (40.75 mg, 0.17 mmol) and (in small portions) sodium borohydride (450.3 mg, 11.9 mmol) were added at 0 ° C. The mixture was stirred at room temperature for 18 hours. Diethylamine (0.183 mL, 1.699 mmol) was then added and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure and aqueous NaHCO ₃ (10%) was added. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 7/3) to give [(S) -3- (4-bromo-2-methoxy-phenyl) -4-hydroxy-butyl] -carbamic acid tert- 405 mg (64% yield) of butyl ester was obtained.

Step 6 (S) -3- (4-Bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester Mesyl chloride (93.7 μL, 1.21 mmol) in DCM (7.5 mL) Of [(S) -3- (4-bromo-2-methoxy-phenyl) -4-hydroxy-butyl] -carbamic acid tert-butyl ester (394 mg, 1.0527 mmol) in an argon atmosphere at −78 ° C. Followed by TEA (0.336 mL, 2.42 mmol). The mixture was stirred at −78 ° C. for 1 hour and then at room temperature for an additional hour. An aqueous solution of NaHCO ₃ (10%) was added and the organic layer was separated and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to give 480 mg of crude methanesulfonic acid (S) -2- (4-bromo-2-methoxy-phenyl) -4-tert-butoxycarbonylamino-butyl ester. This material was dissolved in THF (4 mL) under Ar atmosphere and cooled to 0 ° C. KHMDS (0.5 M in toluene, 2.32 mL, 1.158 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. A saturated solution of NH ₄ Cl was added followed by brine and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 98/2), with an enantiomeric excess of 99% as measured by a chiralcel HPLC column using hexane / i-PrOH (9/1) as the mobile phase. 315 mg (84% yield) of (S) -3- (4-bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.

Step 7 (S) -3- (4-Bromo-2-hydroxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester sodium ethanethiolate (80%, 218.7 mg, 1.704 mmol) was added to DMF (3 To a solution of (S) -3- (4-bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (303 mg, 0.8505 mmol) in 1 mL) under an argon atmosphere. The reaction mixture was heated at 105 ° C. for 3.5 hours and then cooled to 5 ° C. A 10% KHSO ₄ / Na ₂ SO ₄ solution was added until the pH reached 2-3. Water was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (using a gradient of hexane / EtOAc, 90/10 to 85/15) to give (S) -3- (4-bromo-2-hydroxy-phenyl) -pyrrolidine-1 -236 mg (81% yield) of carboxylic acid tert-butyl ester were obtained as a foam.

  (S) -3- (4-Bromo-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was similarly prepared using the appropriate bromobenzoic acid.

  Using the appropriate enantiomeric oxazolidinone in Step 2, (R) -3- (4-bromo-2-hydroxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester and (R) -3- ( 4-Bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was prepared similarly.

Preparation 7
(S) -3- (4-Mercapto-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester The synthetic procedure described in this preparation was performed according to the method shown in Scheme H.

Step 1 (S) -3- [4- (2-Trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 2- (trimethylsilyl) ethanethiol (0.33 mL, 2.1 mmol ), Pd ₂ (dba) ₃ (183.9 mg), Xantphos (231.4 mg) and DIPEA (0.296 mL) were added to (S) -3- (4-bromo-) in 1,4-dioxane (7 mL). To a solution of phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (528 mg, 1.618 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 95-100 ° C. for 20 hours. After cooling to room temperature, a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 94/6) to give (S) -3- [4- (2-trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert -616 mg (quantitative yield) of butyl ester were obtained.

Process 2
( S) -3- (4-Mercapto-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- [4- (2-trimethylsilanyl-ethylsulfanyl) -phenyl] -pyrrolidine-1 A mixture of carboxylic acid tert-butyl ester (613 mg, 1.615 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 10.5 mL) was stirred overnight. Then _10% KHSO 4 / _Na of 2 SO ₄ solution was added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 91/9) to give 288 mg (64% yield) of (S) -3- (4-mercapto-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester. ) Was obtained as a colorless oil.

Preparation 8
3-Chloro-benzenesulfonyl fluoride The synthetic procedure described in this preparation was performed according to the method shown in Scheme I.

Potassium fluoride (2.28 g, 39.4 mmol) was added to a solution of 3-chlorosulfonyl chloride (2.08 g, 9.855 mmol) in 1,4-dioxane (50 mL) under a nitrogen atmosphere. The reaction mixture was heated to reflux for 4 hours, then cooled to 0-5 ° C. and ice water was added. The resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 9/1) to give 1.64 g (86% yield) of 3-chlorosulfonyl fluoride as a colorless oil.

Example 1
3- [4- (3-Ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine and 5- (3-ethylsulfanyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol are described in this preparation. The synthetic procedure was performed according to the method shown in Scheme J.

Step 1 3- [4- (3-Chloro-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester n-BuLi (2.5 M in hexane, 2.76 mL, 6.905 mmol) ) In a solution of 3- (4-bromo-2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (2.05 mg, 5.754 mmol) in THF (2.5 mL) under an argon atmosphere. Added at -78 ° C. After stirring at −78 ° C. for 10 minutes, 3-chlorosulfonyl fluoride (1.13 g, 5.754 mmol) was added to the reaction and the resulting mixture was stirred at −78 ° C. for 1 hour. Then a saturated solution of NH ₄ Cl was added at −78 ° C. and the resulting mixture was allowed to reach room temperature. The mixture was extracted 3 times with EtOAc. The combined organic extracts were washed with water and brine; then dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography (hexane / EtOAc, 7/3) to give 3- [4- (3-chloro-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine. -1-carboxylic acid tert-butyl ester (1.5 g, yield 58%) was obtained as a white foam.

Step 2 3- [4- (3-Ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester and 3- [4- (3-ethylsulfanyl-benzenesulfonyl)- 2-Hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester sodium ethanethiolate (0.698 g, 8.304 mmol) was added to 3- [4- (3-chloro-benzenesulfonyl) in DMF (10 mL). 2-Methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (1.251 g, 2.768 mmol) was added to the solution and the mixture was heated at 100 ° C. for 48 hours. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc / AcOH, 70/30/1) to give 3- [4- (3-ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] as the first fraction. -Pyrrolidine-1-carboxylic acid tert-butyl ester and as the second fraction 3- [4- (3-ethylsulfanyl-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl An ester was obtained.

Step 3 3- [4- (3-Ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine trifluoroacetic acid (1 mL) was added to 3- [4- (3-ethylsulfanyl--) in DCM (3 mL). To a solution of benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.1256 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between NaOH (2M) and DCM. The organic layer was separated, washed with water, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 3- [4- (3-ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine. It was converted to the corresponding hydrochloride salt (white foam, 53 mg) by adding a slight excess of HCl in 1,4-dioxane. MS (M + H) = 378.

  3- [4- (3-Ethylsulfanyl-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester is converted to 5- (3-ethylsulfanyl-benzenesulfonyl) -2-pyrrolidine- Conversion to 3-yl-phenol hydrochloride similarly: melting point = 65.1-70.0 ° C .; MS (M + H) = 364.

  Using the procedure of Example 1, 2-ethylsulfanyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol was similarly prepared: mp = 190.7-192.5 ° C; MS (M + H) = 378.

Example 2
5- (3-ethanesulfonyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol The synthetic procedure described in this example was performed according to the method shown in Scheme K.

Step 1 OXONE ™ (0.663 g, 1 in 3- [4- (3-ethanesulfonyl-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester water (5 mL) 0.078 mmol) was added to a tert-3- [4- (3-ethylsulfanyl-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylate in a mixture of MeOH (5 mL) and acetonitrile (5 mL). To a solution of butyl ester (0.50 g, 1.078 mmol). The reaction mixture was stirred at room temperature for 3 hours, then water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography (hexane / EtOAc, 7/3) to give 3- [4- (3-ethanesulfonyl-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert- 0.369 g (69% yield) of butyl ester was obtained as a white solid.

Step 2 5- (3-ethanesulfonyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol Using the procedure of Step 3 of Example 1, 5- (3-ethanesulfonyl-benzenesulfonyl) -2- Pyrrolidin-3-yl-phenol was prepared as the hydrochloride salt: mp = 124.5-126.7 ° C; MS (M + H) = 396.

  3- [4- (3-ethanesulfonyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine hydrochloride was prepared similarly: melting point = 98.5-100.0 ° C .; MS (M + H) = 410.

Example 3
3- [4- (4-Methoxy-benzenesulfonyl) -2-methyl-phenyl] -1-methyl-pyrrolidine The synthetic procedure described in this example was performed according to the method shown in Scheme L.

Step 1 3- [4- (4-Methoxy-phenylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester tris (dibenzylideneacetone) dipalladium (0) (336 mg, 0.3674 mmol) ), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (425 mg, 0.7347 mmol), 4-methoxy-benzenethiol (361 μL, 2.939 mmol) and DIPEA (0.538 mL, 5.878 mmol). Is added to a solution of 3- (4-bromo-2-methyl-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.939 mmol) in 1,4-dioxane (10 mL). It was. The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 95/5) to give 3- [4- (4-methoxy-phenylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid. 0.91 g (77% yield) of tert-butyl ester was obtained as a white foam.

Step 2 3- [4- (4-Methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester in water (3 mL) OXONE ™ (2.8 g, 4. 554 mmol) of 3- [4- (4-methoxy-phenylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester in a mixture of MeOH (5 mL) and acetonitrile (5 mL). To a solution of (0.91 g, 2.277 mmol). The reaction mixture was stirred at room temperature for 1 hour and then quenched by adding water. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc) to give 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester. 0.845 g (86% yield) was obtained as a white foam.

Step 3 A solution of 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine HCl (4.0 M in 1,4-dioxane, 3.4 mL) was added to 1,4-dioxane (2 mL). The reaction mixture is added to a solution of 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (0.845 g, 1.958 mmol) in Was stirred at room temperature for 3 hours. A solution of NaOH (2.0 M) was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 0.650 g of 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine as white. As a foam: MS (M + H) = 332.

Step 4 A solution of 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -1-methyl-pyrrolidine formaldehyde (water 37%, 1.47 mL, 19.53 mmol) was added to MeOH (2 mL). Into a solution of 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine (0.20 g, 0.6301 mmol) was added and the reaction mixture was heated to reflux for 30 minutes. The mixture was cooled to 0 ° C. and NaBH ₄ (0.833 g, 22.05 mmol) was added slowly. The mixture was allowed to reach room temperature and it was stirred for an additional hour. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM. The organic layer was separated, washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -1-methyl-pyrrolidine 0. 167 g (77% yield) were obtained as a white foam: MS (M + H) = 346.

Example 4
4- [3-Methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol hydrochloride The synthetic procedure described in this example was performed according to the method shown in Scheme M.

Sodium ethanethiolate (94 mg, 1.111 mmol) was added to 3- [4- (4-methoxy-benzenesulfonyl) -2-methyl-phenyl] -1-methyl-pyrrolidine (128 mg, 0.3705 mol) in DMF (2 mL). ) And the reaction mixture was heated at 100 ° C. for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 4- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzene. Sulfonyl] -phenol was obtained as a white foam. The free amine was converted to the corresponding hydrochloride salt (white foam) by adding a slight excess of HCl in 1.4-dioxane: mp = 186.0-187.5 ° C.

Example 5
3- [3-Methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol The synthetic procedure described in this example was performed according to the method shown in Scheme N.

A solution of LAH (1.0 M in THF, 0.51 mL) was added to {3- [4- (3-hydroxy-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} in THF (1 mL). -To a solution of acetic acid tert-butyl ester (85 mg, 0.2036 mmol). The reaction mixture was stirred at reflux for 2 h, it was cooled to room temperature and Na ₂ SO ₄ . 10H ₂ O was added. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 42 mg of 3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol as white Obtained as a foam: MS (M + H) = 332.

Example 6
2- (3-Methoxy-4-pyrrolidin-3-yl-benzenesulfonyl) -benzonitrile The synthetic procedure described in this example was performed according to the method shown in Scheme O.

Step 1 3- [4- (2-Cyano-phenylsulfanyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester Pd ₂ (dba) ₃ (13 mg, 0.01414 mmol), Xantphos (16 mg , 0.02828 mmol), 2-bromobenzonitrile (0.103 mg, 0.5655 mmol) and DIPEA (0.103 mL, 1.131 mmol) in 3- (4-mercapto-) in 1,4-dioxane (10 mL). To a solution of 2-methoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (0.175 g, 0.5655 mmol). The reaction mixture was heated to reflux for 16 hours, then cooled and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 7/3) to give 3- [4- (2-cyano-phenylsulfanyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid. 0.209 g (90% yield) of tert-butyl ester was obtained as a clear oil.

Step 2 3- [4- (2-Cyano-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester in water (5 mL) OXONE ™ (0.470 g, 0. 7636 mmol) of 3- [4- (2-cyano-phenylsulfanyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester in a mixture of MeOH (5 mL) and acetonitrile (5 mL). To a solution of (0.209 g, 0.5091 mmol). The reaction mixture was stirred at room temperature for 3 hours, then water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 7/3) to give 3- [4- (2-cyano-benzenesulfinyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid. 0.215 g of tert-butyl ester (not shown in Scheme O) was obtained as a clear oil.

To 3- [4- (2-cyano-benzenesulfinyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (0.135 mg, 0.3165 mmol) dissolved in DCM (5 mL) was added m. -CPBA (0.115 mg, 0.9495 mmol) was added and the mixture was stirred at room temperature for 6 hours. DCM was added and the resulting mixture was washed with sodium thiosulfate (10% aqueous solution), NaHCO ₃ (saturated aqueous solution), water and brine. The organic phase was then dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 1/1) to give 3- [4- (2-cyano-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid. 0.125 g (89% yield) of tert-butyl ester was obtained as a clear oil.

Step 3 2- (3-Methoxy-4-pyrrolidin-3-yl-benzenesulfonyl) -benzonitrile 3- [4- (2-cyano-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine-1-carboxylic acid The tert-butyl ester was deprotected according to the procedure described in Example 1. The free amine base was converted to the corresponding hydrochloride salt by adding a slight excess of HCl in 1,4-dioxane: mp = 247.8-249.1 ° C.

Example 7
5-Fluoro-3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indole The synthetic procedure described in this example is illustrated in Scheme P. It carried out according to.

Step 1 3- [4- (1-Benzenesulfonyl-5-fluoro-1H-indol-3-ylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester Step 1 of Example 3 Using the procedure of 3- (4-mercapto-2-methyl-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester with 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole To give 3- [4- (1-benzenesulfonyl-5-fluoro-1H-indol-3-ylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 2 3- [4- (1-Benzenesulfonyl-5-fluoro-1H-indole-3-sulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester of Step 2 of Example 3 The procedure is used to oxidize 3- [4- (1-benzenesulfonyl-5-fluoro-1H-indol-3-ylsulfanyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester To 3- [4- (1-benzenesulfonyl-5-fluoro-1H-indole-3-sulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 3 1-Benzenesulfonyl-5-fluoro-3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indole Using the procedure of Example 3, Step 3, 3- [4 -(1-Benzenesulfonyl-5-fluoro-1H-indole-3-sulfonyl) -2-methyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected to give 1-benzenesulfonyl-5- Fluoro-3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indole was obtained. MS (M + H) = 499.

Step 4 5-Benzenesulfonyl-5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indole formaldehyde (37% in water, 0.19 mL, 2 .505 mmol) and sodium cyanoborohydride (63 mg, 1.002 mmol) were added to 1-benzenesulfonyl-5-fluoro-3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) in acetonitrile (3 mL). ) -1H-indole trifluoroacetate (0.305 mg, 0.5011 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours and then buffered to pH 12 by adding 1 M aqueous NaOH. The mixture was extracted with DCM and the combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 1-benzenesulfonyl-5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidine-3- Yl) -benzenesulfonyl] -1H-indole (0.209 g, 81% yield) was obtained as a white foam. MS (M + H) = 513.

Step 5 An aqueous solution of 5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indole NaOH (2M, 0.8 mL) was added to MeOH (1 mL). Solution of 1-benzenesulfonyl-5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indole (0.209 g, 0.4045 mmol) in And the resulting mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidine-3- Yl) -benzenesulfonyl] -1H-indole (0.102 g) was obtained as a white foam. Mp = 86.5-93.5 [deg.] C; MS (M + H) = 378.

Example 8
4- (3-Methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenylamine The synthetic procedure described in this example was performed according to the method shown in Scheme Q.

SnCl ₂ . 2H ₂ O (1.74g, 7.726mmol) in isopropanol (20 mL) solution of 3- [2-methyl-4- (4-nitro-benzenesulfonyl) - - phenyl] - pyrrolidine-1-carboxylic acid tert- butyl ester (0.69 g, 1.545 mmol) (prepared according to the procedure described in Example 3) was added and the mixture was stirred at 75 ° C. for 2 h. The reaction mixture was then cooled to 0 ° C. and saturated NaHCO ₃ solution was added. The resulting gelatinous material was filtered and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 0.407 g (83% yield) of 4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenylamine. Was obtained as a white foam: MS (M + H) = 317.

Example 9
2-Chloro-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol The synthetic procedure described in this example was performed according to the method shown in Scheme R.

Trifluoroacetic acid is added to 3- {4- [3-chloro-4- (4-methoxy-benzyloxy) -benzenesulfonyl] -2-methyl-phenyl} -pyrrolidine-1-carboxylic acid tert in DCM (2 mL). -Butyl ester (prepared according to the procedure described in Example 6) (0.397 g, 0.6939 mmol) was added to a solution. The reaction mixture was stirred at room temperature for 3 hours and then the solvent was evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 0.143 g of 2-chloro-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol (white Which was converted to the corresponding hydrochloride salt by adding a slight excess of HCl in 1,4-dioxane. The hydrochloride salt was recrystallized to give 0.129 g of a white solid: mp = 110.0-112.9 ° C.

Example 10
5- (3-Fluoro-benzenesulfonyl) -2- (S) -pyrrolidin-3-yl-phenol The synthetic procedure described in this example was performed according to the method shown in Scheme S.

Step 1 (S) -3- [4- (3-Fluoro-phenylsulfanyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3-fluorothiophenol (58 μL, 0.681 mmol), Tris (dibenzylideneacetone) dipalladium (0) (77.4 mg, 0.085 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (97.4 mg, 0.170 mmol) and DIPEA ( 0.156 mL, 1.71 mmol) was added to (S) -3- (4-bromo-2-hydroxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester in 1,4-dioxane (4.6 mL). To a solution of (233 mg, 0.681 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to 5 ° C. and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added followed by brine. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered through a celite pad and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / acetone, 9/1) to give (S) -3- [4- (3-fluoro-phenylsulfanyl) -2-hydroxy-phenyl] -pyrrolidine- 187 mg (70% yield) of 1-carboxylic acid tert-butyl ester were obtained as a white foam.

Step 2 (S) -3- [4- (3-Fluoro-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester m-CPBA (226.8 mg, 0.92 mmol) (S) -3- [4- (3-Fluoro-phenylsulfanyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (182.5 mg, 0.469 mmol) in DCM (8 mL). Was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours, then a solution of sodium thisulphate (10%) was added. The organic layer was separated, washed with NaHCO ₃ (10% aqueous solution), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 65/35) to give (S) -3- [4- (3-fluoro-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine- 192 mg (yield 97%) of 1-carboxylic acid tert-butyl ester was obtained.

Step 3 A solution of 5- (3-fluoro-benzenesulfonyl) -2- (S) -pyrrolidin-3-yl-phenol hydrochloride HCl (4M in 1,4-dioxane, 0.63 mL) was added to 1,4- (S) -3- [4- (3-Fluoro-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (177.5 mg, 0.421 mmol) in dioxane (1 mL) To the solution under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 7.5 hours. The reaction mixture was filtered and a white solid was collected, washed with 1,4-dioxane, dried under reduced pressure, and 5- (3-fluoro-benzenesulfonyl) -2- (S) -pyrrolidine-3- 111 mg (yield 74%) of yl-phenol hydrochloride was obtained. Melting point = 239-241 ° C.

  5- (3-Fluoro-benzenesulfonyl) -2- (R) -pyrrolidin-3-yl-phenol was prepared similarly; Mp = 239.0-241.0 ° C.

Example 11
5- [4-((S) -1-Methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indazole The synthetic procedure described in this example was performed according to the method shown in Scheme T.

Step 1 (S) -3- [4- (1H-indazol-5-ylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 5-bromo-1-H-indazole (200.9 mg, 1 0.02 mmol), Pd ₂ (dba) ₃ (115.9 mg), Xantphos (145.9 mg) and DIPEA (0.188 mL) in (S) -3- (4- To a solution of mercapto-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (285 mg, 1.02 mmol) was added under an argon atmosphere. The reaction mixture was heated at 100 ° C. for 18 hours, then cooled to 5 ° C. and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added. The mixture was filtered, the filter cake was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 7/3) to give (S) -3- [4- (1H-indazol-5-ylsulfanyl) -phenyl] -pyrrolidine-1- 252 mg (62% yield) of carboxylic acid tert-butyl ester was obtained.

Step 2 (S) -3- [4- (1H-indazole-5-sulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester
OXONE ™ (627.3 mg, 1.02 mmol) was added to (S) -3- [4- (1H) in a mixture of acetonitrile (3.1 mL), methanol (3.1 mL) and water (2.5 mL). -Indazol-5-ylsulfanyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (201.8 mg, 0.510 mmol) was added. The reaction mixture was stirred vigorously for 4 hours. Water was then added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography (hexane / EtOAc, 1/1) to give (S) -3- [4- (1H-indazole-5-sulfonyl) -phenyl]- 204.5 mg (94% yield) of pyrrolidine-1-carboxylic acid tert-butyl ester were obtained as a colorless oil.

Step 4 5- [4-((S) -1-Methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indazole hydrochloride trifluoroacetic acid (3.4 mL) in DCM (3.4 mL) To a solution of (S) -3- [4- (1H-indazole-5-sulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (193.4 mg, 0.452 mmol) was added under a nitrogen atmosphere. . The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in acetonitrile (4 mL). Formaldehyde (37% in water, 0.181 mL) was added to this material under a nitrogen atmosphere followed by sodium cyanoborohydride (85 mg). The reaction mixture was stirred for 1.5 hours and then a saturated solution of Na ₂ CO ₃ was added. The mixture was extracted with DCM and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude material was dissolved in HCl (2M, 10 mL) and the resulting mixture was stirred for 8 hours. The solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 5- [4-((S) -1-methyl-pyrrolidin-3-yl)- Benzenesulfonyl] -1H-indazole 89.2 mg is obtained, which is treated with 1,4-dioxane (2 mL) and the corresponding hydrochloride salt by adding HCl (4M in 1,4-dioxane, 0.84 mL). Converted to 83.3 mg. MS (M + H) = 342.

Example 12
4- [4-((S) -1-Methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol hydrochloride The synthetic procedure described in this example was performed according to the method shown in Scheme U.

Process 1
(S) -3- {4- [4- (tert-butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl} -pyrrolidine-1-carboxylic acid tert-butyl ester t-butyldimethylchlorosilane (116.55 mg, 0 .773 mmol), TEA (0.1336 mL, 0.975 mmol) and DMAP (9 mg, 0.0736 mmol) were combined with (S) -3- [4- (4-hydroxy-benzenesulfonyl) -phenyl in DCM (5 mL). ] -Pyrrolidine-1-carboxylic acid tert-butyl ester (297 mg, 0.736 mmol) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours and then a solution of 10% KHSO ₄ / Na ₂ SO ₄ was added. The mixture was extracted with DCM and the combined organic extracts were washed with NaHCO ₃ (10% aqueous solution), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 783/17) to give (S) -3- {4- [4- (tert-butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl. } -Pyrrolidine-1-carboxylic acid tert-butyl ester 370.6 mg (97% yield) was obtained as a foam.

Step 2 (S) -3- {4- [4- (tert-Butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl} -1-methyl-pyrrolidine trifluoroacetic acid (5 mL) in DCM (5 mL) (S) -3- {4- [4- (tert-butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl} -pyrrolidine-1-carboxylic acid tert-butyl ester (342 mg, 0.661 mmol) in argon Added under atmosphere. The mixture was stirred at room temperature for 75 minutes and then the solvent was evaporated under reduced pressure. The crude material (482.9 mg) was dissolved in acetonitrile (5 mL) and to the resulting solution was added formaldehyde (37% in water, 0.264 mL, 3.292 mmol) under an argon atmosphere followed by sodium cyanoborohydride. (82.4 mg, 1.316 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours and then buffered to pH 12. The resulting mixture was extracted with DCM and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give (S) -3- {4- [4- (tert-butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl. } 24-Methyl-pyrrolidine 248.2 mg (87% yield) was obtained as a colorless oil that solidified on standing.

Step 3 4- [4-((S) -1-Methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol hydrochloride n-tetrabutylammonium fluoride (1.0 M in THF, 0.593 mL, 0. 59 mmol) was dissolved in (S) -3- {4- [4- (tert-butyl-dimethyl-silanyloxy) -benzenesulfonyl] -phenyl} -1-methyl-pyrrolidine (242 mg, 0) in THF (2 mL). .561 mmol) was added at 0-5 ° C. under an argon atmosphere. The reaction mixture was stirred at 0-5 ° C. for 1 hour and then concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM / MeOH / NH ₄ OH) to give 122 mg of 4- [4-((S) -1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol. It was. The amine (119 mg) was dissolved in isopropanol (2 mL) and treated with HCl (4M in 1,4-dioxane, 0.12 mL, 0.487 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour and the white solid formed was collected by filtration, washed with isopropanol and dried under reduced pressure to give 4- [4-((S) -1-methyl-pyrrolidin-3-yl. ) -Benzenesulfonyl] -phenol hydrochloride 63 mg was obtained. Melting point = 197-199 ° C.

Example 13
2- [5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -ethanol The synthetic procedure described in this example was performed according to the method shown in Scheme V.

Step 1 3- [4- (3-Fluoro-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester methyl bromoacetate (47 μL, 0.495 mmol) followed by potassium carbonate (136 7 mg, 0.99 mmol) was added to 3- [4- (3-fluoro-benzenesulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (198.7 mg) in acetone (5 mL). , 0.471 mmol) was added under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 hours, then filtered and the solvent was evaporated under reduced pressure to give 3- [4- (3-fluoro-benzenesulfonyl) -2-methoxycarbonylmethoxy-phenyl] -pyrrolidine-1. -240.9 mg of carboxylic acid tert-butyl ester were obtained and used in the next step without further purification.

Step 2 3- [4- (3-Fluoro-benzenesulfonyl) -2- (2-hydroxy-ethoxy) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [4- (3-fluoro-benzene) [Sulfonyl) -2-hydroxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg) was dissolved in THF (2 mL) and lithium borohydride (7.94 mg, 0.365 mmol) was added under an argon atmosphere. Added in. The reaction mixture was stirred at room temperature for 6 hours, then cooled to 0-5 ° C. and a solution of 10% KHSO ₄ / Na ₂ SO ₄ was carefully added until pH 2 was reached. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (hexane / EtOAc, 1/1) to give 3- [4- (3-fluoro-benzenesulfonyl) -2- (2-hydroxy-ethoxy) -phenyl]- Pyrrolidine-1-carboxylic acid tert-butyl ester 103 mg (yield 91%) was obtained.

Process 3
A solution of 2- [5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -ethanol HCl (4M in 1,4-dioxane, 0.3 mL, 1.2 mmol) was added to 1, 3- [4- (3-Fluoro-benzenesulfonyl) -2- (2-hydroxy-ethoxy) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0. 1) in 4-dioxane (1 mL). 215 mmol) solution under nitrogen atmosphere. The reaction mixture was stirred for 4 hours and then the solvent was evaporated under reduced pressure to give 82 mg of 2- [5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -ethanol hydrochloride as a foam. Obtained as a product. MS (M + H) = 366.

Example 14
2- [5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -N-methyl-acetamide The synthetic procedure described in this example was performed according to the method shown in Scheme W did.

Step 1 3- [4- (3-Fluoro-benzenesulfonyl) -2-methylcarbamoylmethoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [4- (3-fluoro-benzenesulfonyl) -2 -Methoxycarbonylmethoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, prepared as described in Example 13) and methylamine (2M in THF, 1.2 mL) were sealed. Heated in a tube at 90 ° C. for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure and the crude residue was purified by flash chromatography (hexane / EtOAc, 3/7) to give 3- [4- (3-fluoro-benzenesulfonyl) -2-methyl. 109 mg of carbamoylmethoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester were obtained as a colorless oil.

Process 2
2- [5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -N-methyl-acetamide Using HCl in 1,4-dioxane according to the procedure described in Example 13 3- [4- (3-fluoro-benzenesulfonyl) -2-methylcarbamoylmethoxy-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester is deprotected to give 2- [5- (3-fluoro -Benzenesulfonyl) -2-pyrrolidin-3-yl-phenoxy] -N-methyl-acetamide was obtained as the hydrochloride salt. MS (M + H) = 393.

Example 15
2- {3- [4- (3-Fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -ethanol The synthetic procedure described in this example is illustrated in Scheme X. It carried out according to.

Step 1 {3- [4- (3-Fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -acetic acid methyl ester triethylamine (0.387 mL, 1.533 mmol) and methyl bromoacetate (0 146 mL, 1.533 mmol) to a solution of 3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine (0.445 g, 1.393 mmol) in DCM (5 mL). Added at ° C. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure and the crude residue was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give {3- [4- (3-fluoro- 0.410 g (84% yield) of benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -acetic acid methyl ester was obtained as a yellow oil.

Step 2 2- {3- [4- (3-Fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -ethanol lithium aluminum hydride (1.0 M in THF, 0.51 mL). To a solution of {3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -acetic acid methyl ester (100 mg, 0.2554 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 hour. Water was added slowly and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 2- {3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine-1 7 mg of -yl} -ethanol was obtained. MS (M + H) = 364.

Example 16
2- {3- [4- (3-Fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -acetamide The synthetic procedure described in this example is the method depicted in Scheme Y It carried out according to.

A concentrated solution of ammonium hydroxide (2 mL) was added to {3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -acetic acid methyl ester in methanol (2 mL). (130 mg, 0.3321 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography (DCM / MeOH / NH ₄ OH) to give 2- {3- [4- (3-fluoro-benzenesulfonyl) -2-methyl- 0.102 g of [phenyl] -pyrrolidin-1-yl} -acetamide was obtained as a white foam: MS (M + H) = 377.

Example 17
5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid ethyl ester The synthetic procedure described in this preparation was performed using the procedure in Scheme Z.

Step 1 5-Bromo-2-iodo - benzoic acid ethyl ester 5-Bromo-2-iodo - benzoic acid (25.0g, 76.47mol) _was dissolved at room temperature in CH ₂ Cl ₂ (75ml). Oxalyl chloride (14.5 ml, 152.94 mmol) was added and the mixture was stirred at 40 ° C. for 30 minutes. The mixture was allowed to cool to room temperature and EtOH (6.69 ml, 114.71 mmol) was added. The mixture was concentrated under reduced pressure to give 27.2 g (equivalent) of 5-bromo-2-iodo-benzoic acid ethyl ester as a yellow crystalline solid.

Step 2 3- (4-Bromo-2-ethoxycarbonyl-phenyl) -pyrrole-1-carboxylic acid tert-butyl ester 5-bromo-2-iodo-benzoic acid ethyl ester (3.93 g, 11.07 mmol), tri Isopropylsilanyl-1H-pyrrole-3-boronic acid (2.96 g, 11.07 mmol), PdCl ₂ dppf (443 mg, 0.55 mmol) and CsCO ₃ (4.32 g, 13.28 mmol) were added with DME and water. Dissolved in 100 ml of the mixture (9: 1). The mixture was heated to 80 ° C. overnight. Upon cooling, the mixture was diluted with water and extracted with Et ₂ O. The ether extract was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was immediately diluted with THF. (Boc) ₂ O (2.42 g, 11.07 mmol) was added, followed by TBAF (11.07 ml, 11.07 mmol). The mixture was stirred at room temperature for 2 hours, the mixture was diluted with water and extracted with Et ₂ O. The combined ether extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 3- (4-bromo-2-ethoxycarbonyl-phenyl) -pyrrole-1-carboxylic acid. 1.648 g (37.77%) of tert-butyl ester was obtained as a clear oil which was used in Step 3 without further purification.

Step 3 3- [2-Ethoxycarbonyl-4- (3-fluoro-phenylsulfanyl) -phenyl] -pyrrole-1-carboxylic acid tert-butyl ester 3- (4-bromo-2-ethoxycarbonyl-phenyl) -pyrrole -1-carboxylic acid tert-butyl ester (1.65 g, 4.180 mmol) was dissolved in 25 ml of dioxane. Tris (dibenzylideneacetone) dipalladium (0) (478 mg, 0.522 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (605 mg, 1.044 mmol), and DIPEA (1.82 ml) 10.45 mmol) was added followed by 3-fluorothiophenol (0.353 ml, 4.180 mmol). The mixture was heated to 90 ° C. overnight. The mixture was cooled to 5 ° C. and diluted with pH 2 buffer. Brine was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered through a GF / F filter and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc 9/1) to give tert-butyl 3- [2-ethoxycarbonyl-4- (3-fluoro-phenylsulfanyl) -phenyl] -pyrrole-1-carboxylate. 983 mgs (53.02%) of the ester was obtained as a clear oil.

Step 4 3- [2-Ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrole-1-carboxylic acid tert-butyl ester 3- [2-ethoxycarbonyl-4- (3-fluoro-phenyl) Sulfanyl) -phenyl] -pyrrole-1-carboxylic acid tert-butyl ester (983 mg, 2.226 mmol) was dissolved in 10 ml of a mixture of acetonitrile and MeOH (1: 1). A solution of Oxone (2.053 g, 3.390 mmol) in 5 ml of water was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue is purified by flash chromatography (hexanes / acetone 9/1) to give 3- [2-ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrole-1-carboxylic acid tert- 906 mg (86%) of butyl ester were obtained as a clear oil.

Step 5 3- [2-Ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [2-ethoxycarbonyl-4- (3-fluoro-benzene) (Sulfonyl) -phenyl] -pyrrole-1-carboxylic acid tert-butyl ester (288 mg, 0.608 mmol) was dissolved in 40 ml of MeOH. Pd (OH) ₂ (200 mg) was added and the mixture was placed in a Parr-bomb and stirred for 72 hours under 200 psi of hydrogen. The solution was filtered through celite and the filtrate was concentrated under reduced pressure to yield 290 mg of 3- [2-ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester. Equivalent weight) was obtained as a white crystalline solid.

Step 6 5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid ethyl ester 3- [2-ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1 - carboxylic acid tert- butyl ester (71 mg, 0.149 mmol) _was dissolved in CH 2 _Cl 2 2ml. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure to give 5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid ethyl ester. MS (M + H) = 378.

Example 18
[5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenyl] -methanol The synthetic procedure described in this preparation was performed using the procedure of Scheme AA.

Step 1 3- [4- (3-Fluoro-benzenesulfonyl) -2-hydroxymethyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [2-ethoxycarbonyl-4- (3-fluoro-benzene) Sulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (136 mg, 0.285 mmol) was dissolved in 25 ml of THF. LiBH ₄ (9.3 mg, 0.428 mmol) was added and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding pH 2 buffer and extracted with EtOAc. The combined extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ Cl ₂ / MeOH 95/5) to give 3- [4- (3-fluoro-benzenesulfonyl) -2-hydroxymethyl-phenyl] -pyrrolidine-1-carboxylic acid. 139 mg (quantitative) of tert-butyl ester were obtained as a clear oil.

Step 2 [5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenyl] -methanol 3- [4- (3-fluoro-benzenesulfonyl) -2-hydroxymethyl-phenyl] -pyrrolidine- 1-carboxylic acid tert- butyl ester (55 mg, 0.126 mmol) _was dissolved in CH 2 _Cl 2 2ml. TFA (0.5 ml) was added and the mixture was stirred for 5 hours. The solution was concentrated under reduced pressure to give a compound containing [5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenyl] -methanol; oxalic acid as a brown gum. MS (M + H) = 336.

Example 19
Dimethyl-carbamic acid 5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzyl ester The synthetic procedure described in this preparation was performed using the procedure in Scheme BB.

Step 1 3- [2-Dimethylcarbamoyloxymethyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [4- (3-fluoro-benzenesulfonyl)- 2-Hydroxymethyl-phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (74 mg, 0.170 mmol) was dissolved in 25 ml THF and the mixture was cooled to -78 ° C. LDA (0.102 ml, 0.204 mmol) was added and stirred for 30 minutes. Dimethylcarbamoyl chloride (0.023 ml, 0.255 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ Cl ₂ / MeOH 95/5) to give 3- [2-dimethylcarbamoyloxymethyl-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1- 83 mg (96%) of carboxylic acid tert-butyl ester were obtained as a clear oil.

Step 2 Dimethyl-carbamic acid 5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzyl ester 3- [2-dimethylcarbamoyloxymethyl-4- (3-fluoro-benzenesulfonyl) -phenyl] - pyrrolidine-1-carboxylic acid tert- butyl ester (83mg, 1.638mmol) _was dissolved in CH 2 _Cl 2 3ml. TFA (0.5 ml) was added and the mixture was stirred for 5 hours. The solution was concentrated to 0 under reduced pressure to give dimethyl-carbamic acid 5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzyl ester. MS (M + H) = 407.

Example 20
5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid The synthetic procedure described in this preparation was performed using the procedure of Scheme CC.

Step 1 3- [2-Carboxy-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester 3- [2-ethoxycarbonyl-4- (3-fluoro-benzenesulfonyl) ) -Phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (290 mg, 0.607 mmol) was dissolved in 3 ml of MeOH. LiOH hydrate (76 mg, 1.821 mmol) was dissolved in 1 ml of water, added to the reaction mixture and stirred for 4 hours. MeOH was removed under reduced pressure. The aqueous residue was washed with Et ₂ O and then acidified with 3N HCl to give a white precipitate that was filtered and dried to give 3- [2-carboxy-4- (3- 270 mgs (99%) of fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid tert-butyl ester were obtained as a white powder.

Step 2 5- (3-Fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid 3- [2-carboxy-4- (3-fluoro-benzenesulfonyl) -phenyl] -pyrrolidine-1-carboxylic acid the tert- butyl ester _(75mg, 0.167mmol), was dissolved in CH 2 _Cl 2 3ml. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure. The residue was crystallized from MeOH to give 59 mgs (equivalent) of 5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-benzoic acid as a white powder. MS (M + H) = 350.

Example 17
Formulations Pharmaceutical preparations delivered by various routes are formulated as shown in the table below. As used in the table, “active ingredient” or “active compound” means one or more compounds of formula I.

  The ingredients are mixed and dispensed into capsules containing about 100 mg each. One capsule is almost all of the daily dose.

  The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) using a suitable tablet machine.

  The ingredients are mixed to form a suspension for oral administration.

  The active ingredient is dissolved in a portion of the water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution isotonic. Make the weight of the solution with the rest of the water for injection, filter through a 0.2μ membrane filter and package under sterile conditions.

  The ingredients are melted together, mixed in a steam bath and poured into a mold containing a total weight of 2.5 g.

  Combine all ingredients except water and heat to about 60 ° C. with stirring. Next, a sufficient amount of water is added at about 60 ° C. with vigorous stirring to emulsify the ingredients, and then a sufficient amount of water to add to about 100 g.

Nasal Spray Formulations Several aqueous suspensions containing about 0.025-0.5% active compound are prepared as nasal spray formulations. The formulation optionally includes inert ingredients such as, for example, microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, and the like. Hydrochloric acid may be added to adjust the pH. Nasal spray formulations typically deliver about 50-100 μl of the formulation via a nasal spray metering pump, typically in a single operation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 18
Radioligand Binding Test This example illustrates an in vitro radioligand binding test of a compound of formula I.

The in vitro binding activity of the compounds of the present invention was determined as follows. Dual determination of 5-HT ₆ ligand affinity is performed by competing for [ ³ H] LSD binding in cell membranes derived from HEK293 cells stably expressing recombinant human 5-HT ₆ receptor. It was. The dual determination of 5-HT _2A ligand affinity is determined by [ ³ H] ketanserin (3- (2) in cell membranes derived from CHO-K1 cells stably expressing recombinant human 5-HT _2A receptor. -(4- (4-Fluorobenzoyl) piperidinol) ethyl) -2,4- (1H, 3H) -quinazolinedione). Cell membranes were obtained from the HEK293 cell line by the method described in Monsma et al., Molecular Pharmacology, Vol. 43 pp. 320-327 (1993), and Bonhaus et al., Br J Pharmacol. Jun; 115 (4). : 622-8 (1995) as described in CHO-K1 cell line.

For the assessment of affinity at the 5-HT ₆ receptor, all measurements were made at 37 ° C. in assay buffer at pH 7.4 containing 50 mM Tris-HCl, 10 mM MgSO ₄ , 0.5 mM EDTA, 1 mM ascorbic acid. , In a reaction volume of 250 microliters. For the assessment of affinity at the 5-HT _2A receptor, all measurements were made at 250 microliters at 32 ° C. in assay buffer at pH 7.4 containing 50 mM Tris-HCl, 5 mM ascorbic acid, 4 mM CaCl ₂ . Performed in the reaction volume.

Assay tubes containing [ ³ H] LSD or [ ³ H] ketanserin (5 nM), competing ligand, and membrane in a shaking water bath at 37 ° C. for 75 minutes (for 5-HT ₆ ), or 32 Incubate 60 ° C. (for 5-HT _2A ), filter onto Packard GF-B plates (presoaked with 0.3% PEI) using a Packard 96-well cell harvester, 3 with ice-cold 50 mM Tris-HCl. Washed twice. Bound [ ³ H] LSD or [ ³ H] ketanserin was measured as radioactivity counts per minute using a Packard Topcount.

Replacement of [ ³ H] LSD or [ ³ H] ketanserin from the binding site, concentration-binding data, 4 parameter logistic equation:

(Where Hill is the Hill slope, [ligand] is the concentration of competing radioligand, and IC ₅₀ is the concentration of radioligand giving half of the maximum specific binding of the radioligand) Quantified with The specific binding region is the difference between the Bmax variable and the basal variable.

Using the steps of this example, compounds of formula I were tested and found to be selective 5-HT ₆ antagonists, selective 5-HT _2A antagonists, or both. For example, the compound 4- [3-fluoro-4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -phenol has a pKi of about 10.0 for the 5-HT6 receptor. And the compound 5- (3-ethylsulfanyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol exhibited a pKi of about 9.05 for the 5-HT2A receptor.

  Further biological data according to Example 18 is shown in the following table:

Example 19
Cognitive power enhancement The cognitive power enhancing properties of the compounds of the present invention can be in an object recognition task model which is an animal cognitive power model. Four month old male Wistar rats (Charles River, The Netherlands) were used. Compounds were prepared daily, dissolved in saline and tested by 3 doses. Administration was always done intraperitoneally (injection volume 1 ml / kg) 60 minutes before T1. Scopolamine hydrobromide was injected 30 minutes after compound injection. Two equal test groups consisted of 24 rats and were tested in two experiments. The order of dose studies was randomly determined. Experiments were performed using a double blind protocol. All rats were treated once with each dosing condition. The object recognition test was described in Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats.1: Behavioral data.Behav.Brain Res. 31, 47-59 Was carried out as follows.

  Although the present invention has been described with reference to particular embodiments, it will be understood by those skilled in the art that various modifications can be made and equivalents can be substituted without departing from the spirit and scope of the invention. Should. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, process step, and objective, spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (24)

Formula I:

[Where:
m is 0-4;
n is 0-2;
Ar is optionally substituted aryl or optionally substituted heteroaryl;
R ¹ is:
hydrogen;
Ci- ₆ -alkyl;
Hetero-C _1-6 alkyl; or — (CH ₂ ) _p —X— (CH ₂ ) _q —R ^a ;
here,
X is —C (O) — or —SO ₂ —;
p and q are each independently 0 or 1; and R ^a is:
C _1-6 alkyl;
C _1-6 alkoxy;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
Hydroxy;
amino;
N—C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and each R ² is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero- _Ci-6 -alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 alkyl-amino;
N, N-di-C _1-6 alkylamino;
Hydroxy-C _1-6 alkyl;
_{-O-C (O) -CH (} NH 2) C 1-6 alkyl; or _{- (CH 2) r -Y- (} CH 2) s -Z- (CH 2) t -Q- (CH 2) u It is a -R ^b;
here,
r, s, t and u are each independently 0 or 1;
Y and Q are each independently —O—, —NR ^c — or a bond;
Z is —C (O) — or —SO ₂ —;
R ^b is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ^c is:
Hydrogen; or a compound or a pharmaceutically acceptable salt thereof represented by C _1-6 alkyl. Each R ² is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero- _Ci-6 -alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 alkyl-amino;
N, N-di-C _1-6 alkylamino; or — (CH ₂ ) _r —Y— (CH ₂ ) _s —Z— (CH ₂ ) _t —Q— (CH ₂ ) _u —R ^b ;
here,
r, s, t and u are each independently 0 or 1;
Z is —C (O) — or —SO ₂ —;
X and Y are each independently —O—, —NR ^c — or a bond;
R ^b is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ^c is:
The compound of claim 1, which is hydrogen; or C _1-6 alkyl. Ar is phenyl, indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl, or benzoimidazolyl, each optionally
Halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, nitro, amino, N—C _{1 -6} alkyl - amino, N, N-di _{-C 1-6} alkylamino, -C _{(O) -C 1-6} alkyl, or _{- (CH 2) w -S (} O) x -R d
(Wherein w is 0 or 1, x is 0-2, and R ^d is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, hetero-C _{1- 6} alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino)
3. A compound according to claim 1 or 2 substituted by 1, 2 or 3 substituents selected from. Ar is phenyl, indolyl or indazolyl, each optionally
Halo, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, amino, N—C _1-6 alkyl-amino, N, N-di-C _1-6 Alkylamino, —C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d
Wherein w is 0 or 1, x is 0-2, and R ^d is C _1-6 alkyl, halo-C _1-6 alkyl, amino, C _1-6 alkyl-amino Or N, N-di-C _1-6 alkylamino)
The compound according to any one of claims 1 to 3, which is substituted by 1, 2 or 3 substituents selected from: Ar is optionally substituted 1, 2 or 3 times by halo, C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfanyl, cyano, hydroxy, nitro, amino, or C _1-6 alkyl. The compound according to any one of claims 1 to 4, which is phenyl. 6. A compound according to any one of claims 1 to 5, wherein Ar is phenyl substituted once by halo, _C1-6 alkoxy or hydroxy. Ar is indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl and dihydroindolonyl, each optionally 1 or 2 times by either halo, C _1-6 alkyl, C _1-6 alkoxy, cyano or hydroxy The compound according to any one of claims 1 to 4, which is substituted. The compound according to any one of claims 1 to 7, wherein R ¹ is hydrogen or methyl.   The compound according to any one of claims 1 to 8, wherein n is 2. m is 0 or 1, and R ² is halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkoxy, hydroxy-C _1-6 alkyl, cyano, —O —C (O) —R ^b , —O—CH ₂ —C (O) —R ^b , —C (O) —R ^b or —CH ₂ —C (O) —R ^b (where R ^b is , Hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkoxy, hydroxyl, hetero-C _1-6 alkyl, cyano, amino, C _1-6 alkyl - amino, or N, N-di-a _{-C 1-6} alkylamino), a compound of any one of claims 1 to 9. m is 0 or 1, and ^{R 2} is _{halo, C 1-6 alkyl, C 1-6} alkoxy, or hydroxy compound of claim 1 wherein. The compound is of formula II:

[Where:
v is 0-4;
Each R ³ is independently:
Halo;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Halo-C _1-6 alkoxy;
C _1-6 alkoxy;
Hydroxy;
Hetero-C _1-6 alkyl;
Cyano;
Nitro;
amino;
N—C _1-6 -alkyl-amino;
N, N-di-C _1-6 alkylamino;
-C _{(O) -C 1-6} alkyl; or _{- (CH} 2) be ^{_{w -S (O) x -R d}} ;
here:
w is 0 or 1;
x is 0-2;
R ^d is:
hydrogen;
C _1-6 alkyl;
Halo _{-C 1-6} alkyl;
Hydroxy;
Hetero-C _1-6 alkyl;
amino;
C _1-6 alkyl-amino; or N, N-di-C _1-6 alkylamino; and R ¹ and R ² are as defined in claim 1]. Item 1. The compound according to Item 1. The compound is of formula IIa or IIb:

The compound according to claim 12, wherein v, R ¹ , R ² and R ³ are as defined in claim 12. The compound is of formula III:

[Where:
Ar is indolyl, indazolyl, quinolinyl, pyrrolyl, pyridinyl, pyrimidinyl, dihydroindolonyl or benzoimidazolyl, each of which is optionally halo, C _1-6 alkyl, halo-C _1-6 alkyl, halo-C _{1 -6} alkoxy, C _1-6 alkoxy, hydroxy, hetero-C _1-6 alkyl, cyano, nitro, amino, N-C _1-6 alkyl-amino, N, N-di-C _1-6 alkylamino,- C (O) —C _1-6 alkyl, or — (CH ₂ ) _w —S (O) _x —R ^d
(W is 0 or 1, x is 0-2, R ^d is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy, hetero-C _1-6. Alkyl, amino, C _1-6 alkyl-amino, or N, N-di-C _1-6 alkylamino)
A compound according to claim 1, which is substituted by 1 or 2 substituents independently selected from: and R ¹ and R ² are as described in claim 1 . Ar is 5-indolyl, 3-indolyl or a 5-indazolyl, and is substituted hydroxy, halo or _{C 1-6} alkyl each optionally, claim 14 A compound according. Less than:
3- [4- (3-fluoro-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine,
3- [4- (3-chloro-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine,
3- [4- (3-chloro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine,
3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidine,
5- (3-ethylsulfanyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol,
4- (4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
3- [4- (3-ethylsulfanyl-benzenesulfonyl) -2-methoxy-phenyl] -pyrrolidine,
3- [4- (3-fluoro-benzenesulfonyl) -2-methoxy-phenyl]-(S) -pyrrolidine,
5- (3-ethanesulfonyl-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol,
2- (3-methoxy-4-pyrrolidin-3-yl-benzenesulfonyl) -benzonitrile,
5-benzenesulfonyl-2-pyrrolidin-3-yl-phenol,
5- (3-fluoro-benzenesulfonyl) -2-pyrrolidin-3-yl-phenol,
4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenylamine,
5- (3-fluoro-benzenesulfonyl) -2- (S) -pyrrolidin-3-yl-phenol,
5- (3-fluoro-benzenesulfonyl) -2- (R) -pyrrolidin-3-yl-phenol,
2-methyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl]-(S) -pyrrolidine,
3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl]-(R) -pyrrolidine,
4- (3-methyl-4- (S) -pyrrolidin-3-yl-benzenesulfonyl) -phenol,
4- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
Methyl- [4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenyl] -amine,
2-ethylsulfanyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
4- [3-methyl-4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
4- [4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -1-methyl- (S) -pyrrolidine,
4- (4- (S) -pyrrolidin-3-yl-benzenesulfonyl) -phenol,
3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
5-benzenesulfonyl-2- (S) -pyrrolidin-3-yl-phenol,
2-ethyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
2,6-dimethyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
4- (3-methoxy-4- (S) -pyrrolidin-3-yl-benzenesulfonyl) -phenol,
3- (4-benzenesulfonyl-2-fluoro-phenyl) -pyrrolidine,
2- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -benzonitrile,
5- (4-hydroxy-benzenesulfonyl) -2- (1-methyl- (S) -pyrrolidin-3-yl) -phenol,
4- (3-fluoro-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
2-isopropyl-4- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
4- [3-fluoro-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
4- [3-methoxy-4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
2-ethyl-4- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -phenol,
2- {3- [4- (3-fluoro-benzenesulfonyl) -2-methyl-phenyl] -pyrrolidin-1-yl} -ethanol,
2,6-dimethyl-4- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
5-phenylsulfanyl-2- (S) -pyrrolidin-3-yl-phenol,
2- {3- [4- (3-fluoro-benzenesulfonyl) -2-hydroxy-phenyl]-(S) -pyrrolidin-1-yl} -acetamide,
4- [3-fluoro-4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -phenol,
5-benzenesulfonyl-2- (1-ethanesulfonyl- (S) -pyrrolidin-3-yl) -phenol,
[5- (3-Fluoro-benzenesulfonyl) -2- (S) -pyrrolidin-3-yl-phenoxy] -acetic acid methyl ester,
Propionic acid 5-benzenesulfonyl-2- (S) -pyrrolidin-3-yl-phenyl ester or 2-amino-3-methyl-pentanoic acid 5-benzenesulfonyl-2- (S) -pyrrolidin-3-yl- 2. A compound according to claim 1 selected from any of the phenyl esters. Less than:
5- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indole,
8- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -quinolin-5-ol,
3-methyl-5- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indazole,
5- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indazole,
5- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-benzimidazole,
5- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indazole,
5- (3-methyl-4- (S) -pyrrolidin-3-yl-benzenesulfonyl) -1H-indazole,
3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-pyrrole,
3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indole,
2- (4-pyrrolidin-3-yl-benzenesulfonyl) -pyridine,
5-fluoro-3- [3-methyl-4- (1-methyl-pyrrolidin-3-yl) -benzenesulfonyl] -1H-indole,
5-fluoro-3- (3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl) -1H-indole,
5- [3-Methyl-4- (1-methyl- (S) -pyrrolidin-3-yl) -benzenesulfonyl] -1H-indazole, or 5- [4- (1-methyl- (S) -pyrrolidine- 2. A compound according to claim 1 selected from any of 3-yl) -benzenesulfonyl] -1H-indazole. It is a manufacturing method of the compound as described in any one of Claims 1-17, Comprising:
(A) Formula h:

And the compound of formula i:

A step of obtaining a pyrrolidine compound represented by:
(B) The compound of formula i is then reacted with an aryl thiol in the presence of a palladium catalyst to yield the formula k:

A step of obtaining a thioether represented by:
(C) optionally oxidizing the compound of formula k and deprotecting it by formula Ia:

[Wherein m and R ² are as defined in claim 1].   A compound of formula Ia prepared by the method of claim 18.   A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 17 in admixture with a pharmaceutically acceptable carrier.   18. A compound according to any one of claims 1 to 17 for use as a medicament.   Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament.   For the prevention or treatment of psychosis, schizophrenia, manic depression, neurological disorders, memory impairment, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, food intake disorders, and Huntington's disease 28. Use according to claim 27, wherein   The invention described herein.